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In-silico analysis of phylogenetic relationship and potentially damaging nsSNPs in human SLC2A2 gene
⁎Corresponding author. mamoona.noreen@gmail.com (Mamoona Noreen)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Transport of glucose across the eukaryotic cell membranes is carried out by members of the glucose transporter (GLUT) family which is mainly divided into three classes (I, II and III) on the basis of phylogenetic relationship. In humans, one member of Class I called GLUT2 is encoded by solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2) gene located on third chromosome. Protein mediated glucose movement across cell membranes is made possible through GLUT2 that is a trans-membrane carrier protein. It regulates the entry of glucose and secretion of insulin in the pancreatic cell. It has three isoforms and the longest isoform consists of 524 amino acid. There are 13 extracellular, 12 transmembrane and 5 cytoplasmic domains in human GLUT2. The risk of Fanconi-Bickel syndrome (FBS), diabetes, breast cancer (BC) and Alzheimer disease (AD) is associated with improper functioning of GLUT2. The most frequent form of genetic changes is single nucleotide polymorphism (SNPs). Non synonymous SNPs (nsSNPs) can result in alterations of amino acids and subsequent changes in phenotype. In this study, in-silico analysis was done to find phylogenetic relationship of human GLUT2 protein and possible deleterious effect of nsSNPs of its coding region. Clustal Omega was used to make phylogenetic tree. SIFT, PolyPhen, PROVEAN and SNPeffect were used to predict deleterious or tolerated SNPs. 167 nsSNPs were predicted to be damaging by SIFT, 65 to be possibly damaging and 77 to be probably damaging by PolyPhen. PROVEAN predicted 162 nsSNPs to be neutral and 138 to be deleterious. 101 SNPs were found to be damaging by three algorithms; SIFT, PolyPhen and PROVEAN.
Keywords
GLUT2
SLC2A2 gene
In silico analysis
nsSNP
Phylogenetic analysis
1 Introduction
Glucose is a major energy source and is an important substrate for both protein and lipid synthesis in mammalian cells. Through glycolysis and the citric acid cycle it supplies energy in the form of adenosine tri phosphate (ATP). In the form of nicotinamide adenine dinucleotide phosphate (NADPH), it provides reducing power through the pentose phosphate shunt. Glucose plays a vital role in retaining cellular homeostasis and metabolic functions. For generating ATP molecules, every vertebrate cell depends on the continuous delivery of glucose (Cant et al., 2002). Glucose transport across the plasma membranes is done by two distinct processes depending on the type of cells and tissues. First is facilitative transport that is interceded by a group of facilitative glucose transporters (GLUT) (Mueckler, 1994; Joost and Thorens, 2001) and the other is sodium dependent transport that is interceded by the Na+/glucose linked transporters (SGLT) (Wright, 2001).
GLUTs are proteins of ∼500 amino acids and are estimated to have 12 transmembrane-spanning alpha helices and a single N-linked oligosaccharide. Based on the phylogenetic analysis and sequence similarities 14 members of GLUT family can be divided into three different classes; Class I, II and III (Thorens and Mueckler, 2010; Joost et al., 2002). Class I includes GLUT 1, 2, 3, 4 and 14, class II includes GLUT 5, 7, 9 and 11 while GLUT 6, 8, 10, 12 and 13 are classified as class III (Manolescu et al., 2007). In humans the solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2) gene is located on q26.2 of chromosome 3 (Fig. 1) which encodes GLUT2 protein. There are three isoforms of GLUT2; NP_000331.1, NP_001265587.1 and NP_001265588.1.
Location of GLUT2 on human chromosome. Arrow head shows that GLUT2 occupies 3q26.2 on third human chromosome. (https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC2A2).
The GLUT2 is a transmembrane carrier protein and it permits protein facilitated glucose movement across cell membranes. GLUT2 is involved in discharge of absorbed or reabsorbed glucose and is mainly expressed in the kidney and intestinal absorptive epithelial cells of basolateral membrane (Wright et al., 2003; Kellett and Brot-Laroche, 2005). GLUT2 is also present in the liver, brain and pancreas. It serves as major glucose transporter for the islet cells. As GLUT2 is a high capacity transporter, the concentration of glucose in the cell is directly proportional to the extracellular level of glucose. Enhanced level of intracellular glucose is supposed to increase the ATP/ADP ratio which will shut ATP sensitive potassium channels, depolarize the cells and secrete insulin (Schuit et al., 2001).
In hepatocytes, as a result of gluconeogenesis, GLUT2 supports the uptake of glucose into the blood. It also yields insulin secretion as glucose-sensing functions in the pancreatic β-cell and hypothalamus as low level of glucose stimulated insulin was described in GLUT2 knockout mice (Guillam et al., 1997; Burcelin et al., 2001; Bady et al., 2006). In β-cells of pancreatic islets and hepatocytes, the major glucose transporter is GLUT2. In both cell types, GLUT2 helps the facilitated diffusion of glucose across the cell membranes, and then intracellular glucose metabolism is initiated by the glucose-phosphorylating enzyme, hexokinase IV or glucokinase. In the β-cells, the rate of glucose metabolism controls insulin secretion, whereas in the liver, glucose metabolism and transport are essential to subsequent glycogen synthesis and gluconeogenesis (Meglasson et al., 1986; Thorens et al., 1988).
Fanconi Bickel Syndrome (FBS) is an autosomal recessive disease of glucose metabolism characterized by accumulation of hepatorenal glycogen, Fanconi nephropathy, and impaired use of glucose and galactose (Fanconi, 1949; Santer et al., 1998). The risk of diabetes has been found to be associated with SNPs of SLC2A2 gene in some (Barroso et al., 2003; Alcolado and Alcolado, 1991) but not in other studies (Matsutani et al.,1990). Globally, breast cancer (BC) is the most frequent cancer among women (Ilahi et al., 2016; Noreen et al., 2015a, 2015b). One way to stimulate growth of cancer cells may be fructose metabolism and the expression of GLUT5 and GLUT2 in BC is elevated and helpful in fructose metabolism (Godoy et al., 2006). The increased level of GLUT2 was observed in patients of Alzheimer disease (AD) (Liu et al., 2008).
Diseases susceptibility and development is affected by presence of genetic variations, one very common type of which is single nucleotide polymorphism or SNPs. In DNA, SNPs are found in both exonic and intronic regions (Noreen et al. 2012). Non synonymous SNPs (nsSNPs) residing in exonic region of protein involve amino acid substitution which can result in alteration of structure and functioning of the protein. Thus nsSNPs can play more significant role in diseases development. In this study we predicted the structural and functional effect of potential genetic variations of human SLC2A2 gene by using some sequence and structural homology based algorithms.
2 Materials and methods
2.1 Dataset compilation
National centre for biological information; NCBI (http://www.ncbi. nlm.nih.gov) was accessed. Protein and nucleotide sequences were acquired in FASTA format. Public SNP database named as dbSNP (http://www. ncbi.nlm.nih.gov/SNP), Gene Cards (http://www.genecards.org/) and UniProt (http://www.uniprot.org) were searched to assemble information related to longest isoform of GLUT2 regarding protein sequence. (GLUT2 gene ID: 6514 SNPs NCBI Reference Sequence: NP_000331). The coding region nsSNPs were screened and were subjected to further computational analysis.
2.2 Phylogenetic analysis
To carry out phylogenetic analysis, protein sequence of human GLUT2 (GenBank Accession Number: NP 000331.1) along other 9 species of Hominidae family; Gorilla gorillagorilla (XP_004038053.1), Pongo abelli (XP_002814322.1), Rhinopithecus roxellana (XP_010359570.1), Microcebus murinus (XP_012591846.1), Bos taurus (DAA33241.1), Myotis brandtii (XP_005886638.1), Neomonachus schauinsland (XP_021558267.1), Galeopterus variegates (XP_008586350.1) and Ailuropoda melanoleuca (XP_002920886.1) were retrieved from the NCBI. Protein sequence in FASTA format of all 10 species was obtained and saved. Protein sequence alignment was performed using Clustal Omega (https://www.ebi.ac.uk/Tools/msa/clustalo/). In Clustal Omega, output format “ClustalW with charater counts” was chosen and option of phylogenetic tree was clicked.
2.3 Membrane topology
The number of machine learning algorithms wre used to align the set of protein sequences and clustering of topological data. These approaches or algorithms are transmembrane helices prediction (PHDhtm) (Rost et al. 1996), statistical algorithm TMAP (Persson and Argos 1994) and Hidden Markov models (HMMs) (HMMTOP (Tusnady and Simon, 1998, 2001); TMHMM (Sonnhammer et al., 1998; Krogh et al., 2001). The membrane topology of GLUT2 protein was predicted with the TMHMM program, server 2.0 (http://www.cbs.dtu.dk/services/TMHMM-2.0/).
2.4 Analysis of nsSNPs by SIFT
Sorting Intolerant from Tolerant (SIFT) is an algorithm that forecasts whether substitution of an amino acid influences protein function or not. It is based on the principle that essential amino acids in a protein family remain conserved, and any replacement at these positions is deleterious, which influences function/activity of protein. Protein sequence in FASTA format along substitution of amino acids was used as input at (http://www.blocks.fhcrc.org/sift/SIFT.html). It then considered the normalized probability for the provided substitution at the related position in the alignment. Substitutions with the normalized probability i.e. Tolerance Index (TI) less than 0.05 were forecasted to be intolerant or harmful whereas substitutions with TI higher than 0.05 were predicted to be tolerant (Adzhubei et al., 2010).
2.5 Analysis of nsSNPs by using PolyPhen
PolyPhen-2 is a tool for forecasting of the feasible impact of an amino acid substitution on the protein structure and function (Adzhubei et al., 2010). Automated divinations of this type are vital for interpreting rare genetic variants, which may have potential approach in recent research of human genetics. Its importance in modern research involves identification of rare alleles that generate Mendelian disease (Bamshad et al., 2011), scanning for medically important alleles in an individual’s genome (Ashley et al., 2010), and profiling the spectrum of rare variation uncovered by deep sequencing of large populations (Tennessen et al., 2012).
PolyPhen (http://genetics.bwh.harvard.edu/pph2) utilizes UniProtKB database which is used as source of reference. Protein sequence of GLUT2 in FASTA format and position of protein sequence was entered. AA1 wild type (query sequence) as well as substitution reside AA2 were selected. Two pair’s datasets were used. First pair of HumDiv and the second pair; HumVar were compiled in UniProt database.
2.6 Analysis of nsSNPs by using PROVEAN
PROVEAN is not only effective to predict single amino acid change but it can also perform task for other changes in the protein sequence including indels (deletion and insertion) (Choi et al., 2012). The PROVEAN web server (http://provean.jcvi.org) gives online approach for the functioning of distribution for the software package of stand-alone. Its major role is to give divination from any of organism’s protein sequence. It takes the sequence of protein and variation of amino acid as input. BLAST search was done to recognize the homologous sequence and produce the PROVEAN result. Generally the BLAST search took 10–20 min to produce the divination for a provided protein query. Sequence identifiers list for supporting sequences and clustering data was stored in database. Focused on sequence of query protein consecutive prediction data for supporting sequences were indexed.
2.7 Analysis of nsSNPs by using SNPeffect
SNPeffect (De Baets et al., 2012) was used to predict the molecular phenotypic influence of nsSNPs lying in coding region of GLUT2 protein. It works beyond the scores got on conservational basis and mainly emphasizes to map the effect of SNPs on the capability of cells to uphold suitable concentration of the properly folded proteins in appropriate cellular region i.e. protein homeostasis landscape (Powers et al., 2009). For this assessment, wild type protein sequence in FASTA format along with each of its variants was given to the SNPeffect server (http://snpeffect.switchlab.org) for analysis. Homology threshold was fixed to 90%. It uses TANGO (Fernandez-Escamilla et al., 2004) which forecasts the regions in given protein sequence that are prone to aggregation and calculated TANGO score with wild and variant amino acid. On the basis of TANGO score difference (dTANGO), the server assesses effect of these variants on protein aggregation. Aggregate morphology is more distinctively evaluated by WALTZ server (Maurer-Stroh et al., 2010) that forecasts amyloid-forming regions in given protein sequence with accuracy and specificity on basis of dWALTZ score. Chaperone binding propensity is forecasted by LIMBO (Van Durme et al., 2009) for the Hsp70 chaperones and effect of variant is determined by dLIMBO score. SNPeffect also uses high resolution crystal structure of proteins from Protein Data Bank (PDB) (Deshpande et al., 2005) and models the variants using the empirical force field FoldX (version 2.5) (Schymkowitz et al., 2005) to determine possible effects on stability and binding properties of given protein.
3 Results
3.1 Phylogenetic analysis
Evolutionary relationship of GLUT2 protein among 10 different species of primates was carried out using human GLUT2 protein as a reference sequence (Fig. 2). The phylogenetic tree generated from Clustal Omega helps to understand the evolutionary relationship of GLUT2 among different species. Evolutionary tree demonstrates that GLUT2 of human and Pongo abelli lie close to each other whereas that of Bos taurusis most distant from human.
Phylogenetic analysis of human GLUT2 protein. A phylogenetic tree of the amino acid sequences of GLUT2 protein was constructed using the Clustal Omega.
3.2 Membrane topology
A significant server TMHMM was used to predict the significant features of helices in transmembrane protein and GLUT2 was found to comprise of 12 predicted transmembrane helices with intracellular amino (N-terminal) and carboxyl (C-termini) in cytosol. It also contains extracellular and intracellular loops which are located between the segments of 1st and 2nd transmem brane domains and between 6th and 7th transmembrane segments (Fig. 3). While, the remaining transmembrane segments from seven to twelve have ability to perform transportation of fructose and glucose to the membrane.
Toplogy prediction of human GLUT2 protein. The human GLUT2 protein comprises of 12 predicted transmembrane helices with intracellular amino (N-terminal) and carboxyl (C-termini) in cytosol. It also contains extracellular and intracellular loops which are located between the segments of 1st and 2nd transmembrane domains and between 6th and 7th transmembrane segments.
3.3 Distribution of SNPs in GLUT2 protein
In the human SLC2A2 gene the non coding region of gene contains 6,628 SNPs in which 83 SNPs were near 3′gene, 340 in 3′UTR, 427 SNPs in 5′ near gene, 62 in 5′UTR and in the intron 5716 SNPs were found (Fig. 4). While the coding region contained 484 SNPs in which 137 SNPs were synonymous, 293 were nsSNPs, 21 were frameshifts; (rs766082034), (rs1447936042), (rs769888108), (rs1255595607), (rs776307487), (rs1162215911), (rs771361095), (rs1326032349), (rs1350704340), (rs1290975016), (rs765132996), (rs1181030797), (rs771799491), (rs746178753), (rs1316522125), (rs748296868), (rs34066960), (rs1174349159), (rs1384674663),(rs1386374799) and (rs1290412048). 11 were nonsense; (rs774841662), (rs771477447), (rs1475086161), (rs1114167428), (rs753629940), (rs773581866), (rs121909746), (rs121909743), (rs121909742), (rs121909745) and (rs1379944645). Out of 7 SNPs, 4 were inframe deletion; (rs772999215), (rs1169887677), (rs763620441), (rs774721090) and 3 were inframe insertion; (rs1161394690), (rs1463507753) and (rs749789723). 10 (rs1294679246), (rs756163471), (rs371977235), (rs1240053337), (rs756874949), (rs1303795800), (rs1281471314), (rs985090030), (rs757587931), (rs867530965) were donor and 4 (rs754220999), (rs1318756243), (rs776248984), (rs1230247311) were acceptor shown (Fig. 5). (rs749789723) SNPs also contain stop gained. 1 SNPs was stop lost (rs750463981). 10 additional SNPs were detected by dbSNP in which 4 SNPs; (rs766082034), (rs1255595607), (rs1162215911), (rs746178753) were frameshifts and 6; (rs766762468), (rs1800572), (rs777020657), (rs867996396), (rs121909747), (rs1309197020) were nsSNPs (Table 1)
Distribution of SNPs in human GLUT2 Protein.
Distribution of nsSNPs in coding region of GLUT2 protein.
| dbSNP id | Function | dbSNPallele | Codonpos. | mRNApos. | Proteinresidue | Amino acidpos |
|---|---|---|---|---|---|---|
| rs759495940 | nsSNPs | G /A | 3 | 312 | Met [M]/Ile [I] | 1 |
| rs773205789 | nsSNPs | A /C | 1 | 313 | Thr [T]/Pro [P] | 2 |
| rs200073044 | nsSNPs | G /C | 1 | 319 | Asp [D]/His [H] | 4 |
| rs1372689853 | nsSNPs | A /G | 1 | 322 | Lys [K]/Glu [E] | 5 |
| rs767313610 | nsSNPs | G /A | 1 | 325 | Val [V]/Ile [I] | 6 |
| rs369700669 | nsSNPs | C /A | 2 | 329 | Thr [T]/Asn [N] | 7 |
| rs766082034 | frame shift | G /- | 3 | 333 | Thr [T]/Pro [P] | 9 |
| rs766082034 | frameshift | G/- | 3 | 333 | (Gly)G/(Gly)G | 9 |
| rs1181030797 | frame shift | G /- | 1 | 340 | Val [V]/Phe [F] | 11 |
| rs1481905618 | nsSNPs | C /A | 3 | 345 | Phe [F]/Leu [L] | 12 |
| rs1247912820 | nsSNPs | C /A | 2 | 347 | Thr [T]/Asn [N] | 13 |
| rs1247912820 | nsSNPs | C /G | 2 | 347 | Thr [T]/Ser [S] | 13 |
| rs372441014 | nsSNPs | G /C | 1 | 349 | Val [V]/Leu [L] | 14 |
| rs766364438 | nsSNPs | T /C | 2 | 353 | Ile [I]/Thr [T] | 15 |
| rs1463507753 | INFRAME INSERTION | TCA | 1 | 355 | Ile[I] /IleIle[II] | 15 |
| rs867315854 | nsSNPs | G /A | 1 | 358 | Ala [A]/Thr [T] | 17 |
| rs761992056 | nsSNPs | G /A | 2 | 368 | Gly [G]/Asp [D] | 20 |
| rs369781481 | nsSNPs | C /A | 3 | 375 | Phe [F]/Leu [L] | 22 |
| rs1409436045 | nsSNPs | T /A | 2 | 380 | Phe [F]/Tyr [Y] | 24 |
| rs1049223265 | nsSNPs | T /C | 2 | 392 | Ile [I]/Thr [T] | 28 |
| rs1437312005 | nsSNPs | G /A | 1 | 394 | Gly [G]/Ser [S] | 29 |
| rs1437312005 | nsSNPs | G /C | 1 | 394 | Gly [G]/Arg [R] | 29 |
| rs775531825 | nsSNPs | A /G | 2 | 404 | Asn [N]/Ser [S] | 32 |
| rs143528640 | nsSNPs | G /A | 1 | 406 | Ala [A]/Thr [T] | 33 |
| rs746158263 | nsSNPs | C /A | 1 | 409 | Pro [P]/Thr [T] | 34 |
| rs774841662 | nonsense | C/ T | 1 | 412 | Gln [Q]/ | 35 |
| rs1158195535 | nsSNPs | C /A | 1 | 415 | Gln [Q]/Lys [K] | 36 |
| rs1158195535 | nsSNPs | C /G | 1 | 415 | Gln [Q]/Glu [E] | 36 |
| rs1451394300 | nsSNPs | G /A | 1 | 418 | Val [V]/Ile [I] | 37 |
| rs1477523180 | nsSNPs | A /C | 1 | 421 | Ile [I]/Leu [L] | 38 |
| rs1360464436 | nsSNPs | T /A | 2 | 422 | Ile [I]/Lys [K] | 38 |
| rs1176350402 | nsSNPs | T /C | 2 | 425 | Ile [I]/Thr [T] | 39 |
| rs772999215 | Inframe Deletion | II [ATA] > I [] | 1 | 424 | IleIle[II] / Ile [I] | 39 |
| rs758670698 | nsSNPs | G /T | 2 | 437 | Arg [R]/Ile [I] | 43 |
| rs760618624 | nsSNPs | C /T | 1 | 439 | His [H]/Tyr [Y] | 44 |
| rs775791143 | nsSNPs | G /A | 1 | 442 | Val [V]/Ile [I] | 45 |
| rs149108283 | nsSNPs | T /A | 2 | 443 | Val [V]/Asp [D] | 45 |
| rs149108283 | nsSNPs | T /C | 2 | 443 | Val [V]/Ala [A] | 45 |
| rs1159338702 | nsSNPs | G /A | 1 | 448 | Gly [G]/Ser [S] | 47 |
| rs561765982 | nsSNPs | G /A | 1 | 451 | Val [V]/Ile [I] | 48 |
| rs983907950 | nsSNPs | C /T | 1 | 454 | Pro [P]/Ser [S] | 49 |
| rs1211075508 | nsSNPs | T /C | 2 | 458 | Leu [L]/Pro [P] | 50 |
| rs1311902495 | nsSNPs | G /A | 1 | 463 | Asp [D]/Asn [N] | 52 |
| rs1311902495 | nsSNPs | G /T | 1 | 463 | Asp [D]/Tyr [Y] | 52 |
| rs771477447 | nonsense | C /T | 1 | 466 | Arg [R]/ | 53 |
| rs771477447 | nsSNPs | C /G | 1 | 466 | Arg [R]/Gly [G] | 53 |
| rs145210664 | nsSNPs | G /A | 2 | 467 | Arg [R]/Gln [Q] | 53 |
| rs546539032 | nsSNPs | A /C | 3 | 471 | Lys [K]/Asn [N] | 54 |
| rs747555903 | nsSNPs | G /A | 1 | 487 | Val [V]/Ile [I] | 60 |
| rs1447936042 | frame shift | - /(26 bp) | 1 | 490 | Ile [I]/Thr [T] | 61 |
| rs977284195 | nsSNPs | T /C | 2 | 491 | Ile [I]/Thr [T] | 61 |
| rs780903829 | nsSNPs | C /G | 3 | 492 | Ile [I]/Met [M] | 61 |
| rs1373290524 | nsSNPs | G /C | 2 | 497 | Ser [S]/Thr [T] | 63 |
| rs1310901426 | nsSNPs | A /G | 1 | 499 | Thr [T]/Ala [A] | 64 |
| rs1169887677 | Inframe Deletion | INS [ATCA] / [ACA] | 2 | 491 | INS (IleAsnSer) / () | 61 |
| rs1354126805 | nsSNPs | C /G | 2 | 500 | Thr [T]/Arg [R] | 64 |
| rs754585542 | nsSNPs | G /A | 1 | 502 | Asp [D]/Asn [N] | 65 |
| rs1217666649 | nsSNPs | T /A | 3 | 504 | Asp [D]/Glu [E] | 65 |
| rs1391257598 | nsSNPs | C /A | 1 | 511 | Pro [P]/Thr [T] | 68 |
| rs7637863 | nsSNPs | C /T | 2 | 512 | Pro [P]/Leu [L] | 68 |
| rs779977931 | nsSNPs | C /A | 2 | 515 | Thr [T]/Lys [K] | 69 |
| rs1182852354 | nsSNPs | A /G | 1 | 517 | Ile [I]/Val [V] | 70 |
| rs750405382 | nsSNPs | A /G | 1 | 529 | Met [M]/Val [V] | 74 |
| rs1207297111 | nsSNPs | A /G | 1 | 532 | Asn [N]/Asp [D] | 75 |
| rs1342979475 | nsSNPs | A /C | 2 | 533 | Asn [N]/Thr [T] | 75 |
| rs1274084408 | nsSNPs | C /G | 1 | 535 | Pro [P]/Ala [A] | 76 |
| rs778655073 | nsSNPs | C /T | 2 | 542 | Pro [P]/Leu [L] | 78 |
| rs769888108 | frame shift | C /- | 2 | 548 | Pro [P]/Leu [L] | 80 |
| rs549263048 | nsSNPs | T /C | 1 | 550 | Trp [W]/Arg [R] | 81 |
| rs531049536 | nsSNPs | G /T | 3 | 552 | Trp [W]/Cys [C] | 81 |
| rs150851401 | nsSNPs | G /A | 1 | 556 | Glu [E]/Lys [K] | 83 |
| rs766762468 | nsSNPs | C /G | 2 | 566 | Thr [T]/Ser [S] | 86 |
| rs766762468 | nsSNPs | C/T | 2 | 566 | T (Thr) > I (Ile) | 86 |
| rs763255363 | nsSNPs | G /T | 1 | 571 | Ala [A]/Ser [S] | 88 |
| rs144715667 | nsSNPs | A /G | 1 | 586 | Ile [I]/Val [V] | 93 |
| rs1415169647 | nsSNPs | T /G | 2 | 593 | Met [M]/Arg [R] | 95 |
| rs1407375423 | nsSNPs | G /T | 3 | 600 | Trp [W]/Cys [C] | 97 |
| rs1800572 | nsSNPs | G /A | 1 | 610 | Val [V]/Ile [I] | 101 |
| rs1800572 | nsSNPs | G/C | 1 | 610 | Val [V] / Leu [L] | 101 |
| rs770135219 | nsSNPs | T /C | 2 | 611 | Val [V]/Ala [A] | 101 |
| rs1399091893 | nsSNPs | C /T | 2 | 623 | Ala [A]/Val [V] | 105 |
| rs1332764085 | nsSNPs | G /A | 1 | 625 | Val [V]/Ile [I] | 106 |
| rs5400 | nsSNPs | C /T | 2 | 638 | Thr [T]/Ile [I] | 110 |
| rs377238940 | nsSNPs | G /C | 1 | 640 | Ala [A]/Pro [P] | 111 |
| rs1475086161 | nonsense | C /G | 2 | 644 | Ser [S]/ | 112 |
| rs1255595607 | frame shift | C /- | 3 | 648 | Phe [F]/Leu [L] | 114 |
| rs1255595607 | frame shift | C /- | 3 | 648 | Phe [F]/ Phe [F] | 114 |
| rs768407637 | nsSNPs | G /T | 2 | 656 | Gly [G]/Val [V] | 116 |
| rs753980727 | nsSNPs | G /T | 3 | 660 | Trp [W]/Cys [C] | 117 |
| rs746632604 | nsSNPs | G /C | 2 | 665 | Gly [G]/Ala [A] | 119 |
| rs772002572 | nsSNPs | C /T | 2 | 671 | Thr [T]/Ile [I] | 121 |
| rs1476520648 | nsSNPs | T /A | 2 | 683 | Ile [I]/Asn [N] | 125 |
| rs760201098 | nsSNPs | C /A | 2 | 689 | Ala [A]/Asp [D] | 127 |
| rs1267904495 | nsSNPs | T /C | 2 | 692 | Met [M]/Thr [T] | 128 |
| rs1212980167 | nsSNPs | G /C | 3 | 693 | Met [M]/Ile [I] | 128 |
| rs367856967 | nsSNPs | T /C | 2 | 698 | Val [V]/Ala [A] | 130 |
| rs970550665 | nsSNPs | C /G | 2 | 701 | Ala [A]/Gly [G] | 131 |
| rs775283150 | nsSNPs | A /T | 1 | 706 | Ile [I]/Phe [F] | 133 |
| rs913419413 | nsSNPs | T /G | 2 | 710 | Leu [L]/Arg [R] | 134 |
| rs771843187 | nsSNPs | T /C | 1 | 712 | Ser [S]/Pro [P] | 135 |
| rs144125084 | nsSNPs | G /C | 1 | 718 | Val [V]/Leu [L] | 137 |
| rs993833041 | nsSNPs | T /C | 2 | 719 | Val [V]/Ala [A] | 137 |
| rs1300072764 | nsSNPs | G /A | 2 | 722 | Gly [G]/Glu [E] | 138 |
| rs778548964 | nsSNPs | C /T | 1 | 727 | Leu [L]/Phe [F] | 140 |
| rs776307487 | frame shift | T /- | 2 | 728 | Leu [L]/Pro [P] | 140 |
| rs1016384738 | nsSNPs | T /A | 2 | 734 | Met [M]/Lys [K] | 142 |
| rs770941010 | nsSNPs | G /C | 1 | 736 | Gly [G]/Arg [R] | 143 |
| rs777718289 | nsSNPs | G /A | 2 | 752 | Gly [G]/Glu [E] | 148 |
| rs777718289 | nsSNPs | G /T | 2 | 752 | Gly [G]/Val [V] | 148 |
| rs372621339 | nsSNPs | C /G | 2 | 755 | Pro [P]/Arg [R] | 149 |
| rs747025551 | nsSNPs | T /C | 2 | 764 | Ile [I]/Thr [T] | 152 |
| rs376064965 | nsSNPs | C /T | 1 | 766 | Leu [L]/Phe [F] | 153 |
| rs1188886679 | nsSNPs | A /C | 1 | 769 | Ile [I]/Leu [L] | 154 |
| rs1188886679 | nsSNPs | A /G | 1 | 769 | Ile [I]/Val [V] | 154 |
| rs192720796 | nsSNPs | T /A | 2 | 770 | Ile [I]/Lys [K] | 154 |
| rs763620441 | INFRAME DELETION | ILI [CTTATA] / I [] | 1 | 766 | IleLeuIle [ILI] / Ile [I] | 153 |
| rs910976682 | nsSNPs | C /T | 2 | 776 | Ala [A]/Val [V] | 156 |
| rs750836049 | nsSNPs | G /C | 1 | 778 | Gly [G]/Arg [R] | 157 |
| rs1278964539 | nsSNPs | G /A | 2 | 782 | Arg [R]/Lys [K] | 158 |
| rs1231468128 | nsSNPs | T /A | 2 | 797 | Leu [L]/Gln [Q] | 163 |
| rs1445887606 | nsSNPs | T /C | 1 | 799 | Tyr [Y]/His [H] | 164 |
| rs1271546287 | nsSNPs | T /C | 2 | 812 | Ile [I]/Thr [T] | 168 |
| rs760095835 | nsSNPs | G /A | 2 | 818 | Gly [G]/Asp [D] | 170 |
| rs1335888503 | nsSNPs | G /C | 1 | 823 | Val [V]/Leu [L] | 172 |
| rs1293130515 | nsSNPs | T /C | 2 | 830 | Met [M]/Thr [T] | 174 |
| rs1019696977 | nsSNPs | A /G | 1 | 835 | Ile [I]/Val [V] | 176 |
| rs144822218 | nsSNPs | G /A | 1 | 838 | Gly [G]/Ser [S] | 177 |
| rs759047405 | nsSNPs | G /A | 2 | 839 | Gly [G]/Asp [D] | 177 |
| rs1441606652 | nsSNPs | C /T | 2 | 848 | Ala [A]/Val [V] | 180 |
| rs368626129 | nsSNPs | G /A | 1 | 856 | Ala [A]/Thr [T] | 183 |
| rs368626129 | nsSNPs | G /T | 1 | 856 | Ala [A]/Ser [S] | 183 |
| rs771799491 | frame shift | G /- | 2 | 866 | Gly [G]/Glu [E] | 186 |
| rs200213178 | nsSNPs | G /A | 1 | 868 | Ala [A]/Thr [T] | 187 |
| rs200213178 | nsSNPs | G /C | 1 | 868 | Ala [A]/Pro [P] | 187 |
| rs748052042 | nsSNPs | C /T | 1 | 871 | Leu [L]/Phe [F] | 188 |
| rs1412289847 | nsSNPs | G /A | 1 | 874 | Gly [G]/Ser [S] | 189 |
| rs776498787 | nsSNPs | G /A | 2 | 875 | Gly [G]/Asp [D] | 189 |
| rs779065938 | nsSNPs | C /G | 1 | 889 | Leu [L]/Val [V] | 194 |
| rs1469335096 | nsSNPs | G /A | 1 | 892 | Ala [A]/Thr [T] | 195 |
| rs771182536 | nsSNPs | T /A | 2 | 896 | Ile [I]/Asn [N] | 196 |
| rs771182536 | nsSNPs | T /C | 2 | 896 | Ile [I]/Thr [T] | 196 |
| rs121909741 | nsSNPs | G /A | 1 | 898 | Val [V]/Ile [I] | 197 |
| rs149460434 | nsSNPs | C /A | 2 | 902 | Thr [T]/Lys [K] | 198 |
| rs149460434 | nsSNPs | C /T | 2 | 902 | Thr [T]/Met [M] | 198 |
| rs1276756236 | nsSNPs | C /A | 1 | 910 | Leu [L]/Ile [I] | 201 |
| rs779591826 | nsSNPs | T /G | 3 | 924 | Ile [I]/Met [M] | 205 |
| rs1262860274 | nsSNPs | T /C | 2 | 926 | Ile [I]/Thr [T] | 206 |
| rs1186359171 | nsSNPs | G /A | 1 | 928 | Gly [G]/Ser [S] | 207 |
| rs1114167428 | nonsense | G /T | 1 | 934 | Glu [E]/ | 209 |
| rs1215469128 | nsSNPs | T /C | 2 | 944 | Leu [L]/Ser [S] | 212 |
| rs1347267249 | nsSNPs | A /C | 1 | 949 | Asn [N]/His [H] | 214 |
| rs573292685 | nsSNPs | A /G | 2 | 950 | Asn [N]/Ser [S] | 214 |
| rs764799427 | nsSNPs | A /T | 2 | 956 | Asp [D]/Val [V] | 216 |
| rs753629940 | nonsense | G /A | 3 | 963 | Trp [W]/ | 218 |
| rs1380319602 | nsSNPs | T /A | 2 | 968 | Ile [I]/Asn [N] | 220 |
| rs760641937 | nsSNPs | G /C | 2 | 977 | Gly [G]/Ala [A] | 223 |
| rs1413841367 | nsSNPs | T /C | 2 | 980 | Leu [L]/Pro [P] | 224 |
| rs771075989 | nsSNPs | G /A | 1 | 988 | Val [V]/Met [M] | 227 |
| rs773581866 | nonsense | C /T | 1 | 991 | Arg [R]/ | 228 |
| rs773581866 | nsSNPs | C /G | 1 | 991 | Arg [R]/Gly [G] | 228 |
| rs770126214 | nsSNPs | C /A | 1 | 1000 | Leu [L]/Ile [I] | 231 |
| rs1374154306 | nsSNPs | T /A | 2 | 1013 | Leu [L]/Gln [Q] | 235 |
| rs748588515 | nsSNPs | C /T | 1 | 1015 | Leu [L]/Phe [F] | 236 |
| rs1162215911 | frame shift | CT /- | 3 | 1017 | Phe [F]/Leu [L] | 238 |
| rs1162215911 | frame shift | CT /- | 3 | 1017 | Leu [L] /Leu[L] | 238 |
| rs757087261 | nsSNPs | T /A | 1 | 1021 | Phe [F]/Ile [I] | 238 |
| rs777020657 | nsSNPs | T /G | 2 | 1022 | Phe [F]/Cys [C] | 238 |
| rs777020657 | nsSNPs | T/C | 2 | 1022 | Phe [F] /Ser[S] | 238 |
| rs769089021 | nsSNPs | G /A | 2 | 1034 | Ser [S]/Asn [N] | 242 |
| rs780381836 | nsSNPs | A /G | 1 | 1039 | Arg [R]/Gly [G] | 244 |
| rs1480881050 | nsSNPs | T /C | 1 | 1042 | Tyr [Y]/His [H] | 245 |
| rs1250722271 | nsSNPs | T /C | 1 | 1048 | Tyr [Y]/His [H] | 247 |
| rs1158317020 | nsSNPs | A /T | 2 | 1049 | Tyr [Y]/Phe [F] | 247 |
| rs867996396 | nsSNPs | T /A | 2 | 1052 | Ile [I]/Asn [N] | 248 |
| rs867996396 | nsSNPs | T/C | 2 | 1052 | Ile [I] / Thr [T] | 248 |
| rs536261161 | nsSNPs | G /C | 3 | 1056 | Lys [K]/Asn [N] | 249 |
| rs745373269 | nsSNPs | G /A | 1 | 1060 | Asp [D]/Asn [N] | 251 |
| rs745373269 | nsSNPs | G /C | 1 | 1060 | Asp [D]/His [H] | 251 |
| rs1367431424 | nsSNPs | A /C | 2 | 1064 | Glu [E]/Ala [A] | 252 |
| rs865881030 | nsSNPs | G /A | 1 | 1066 | Glu [E]/Lys [K] | 253 |
| rs778607566 | nsSNPs | A /G | 2 | 1067 | Glu [E]/Gly [G] | 253 |
| rs1309254226 | nsSNPs | A /C | 3 | 1068 | Glu [E]/Asp [D] | 253 |
| rs777225980 | nsSNPs | C /A | 3 | 1086 | Ser [S]/Arg [R] | 259 |
| rs76026576 | nsSNPs | G /T | 3 | 1089 | Leu [L]/Phe [F] | 260 |
| rs746178753 | frame shift | AG /- | 3 | 1101 | Gly [G]/Ile [I] | 265 |
| rs746178753 | frame shift | AG /- | 3 | 1101 | Arg [R]/ Arg[R] | 265 |
| rs1490504926 | nsSNPs | G /A | 1 | 1108 | Asp [D]/Asn [N] | 267 |
| rs935009475 | nsSNPs | T /A | 3 | 1113 | Asp [D]/Glu [E] | 268 |
| rs774721090 | Inframe Deletion | DD [GATG] / D [GTC] | 2 | 1112 | AspAsp[DD]/ Asp [D] | 268 |
| rs140285191 | nsSNPs | G /A | 1 | 1123 | Asp [D]/Asn [N] | 272 |
| rs140285191 | nsSNPs | G /T | 1 | 1123 | Asp [D]/Tyr [Y] | 272 |
| rs754932741 | nsSNPs | G /A | 3 | 1137 | Met [M]/Ile [I] | 276 |
| rs750579210 | nsSNPs | A /G | 1 | 1138 | Arg [R]/Gly [G] | 277 |
| rs1304842107 | nsSNPs | A /C | 1 | 1141 | Lys [K]/Gln [Q] | 278 |
| rs765426962 | nsSNPs | A /C | 2 | 1142 | Lys [K]/Thr [T] | 278 |
| rs761756532 | nsSNPs | A /C | 3 | 1143 | Lys [K]/Asn [N] | 278 |
| rs771361095 | frame shift | -/A | 1 | 1147 | Arg [R]/Lys [K] | 280 |
| rs1329237779 | nsSNPs | G /A | 1 | 1153 | Glu [E]/Lys [K] | 282 |
| rs1384542256 | nsSNPs | A /C | 2 | 1154 | Glu [E]/Ala [A] | 282 |
| rs776912318 | nsSNPs | A /C | 1 | 1162 | Ser [S]/Arg [R] | 285 |
| rs776912318 | nsSNPs | A /T | 1 | 1162 | Ser [S]/Cys [C] | 285 |
| rs121909746 | nonsense | C /T | 1 | 1168 | Gln [Q]/ | 287 |
| rs764161243 | nsSNPs | A /C | 2 | 1172 | Lys [K]/Thr [T] | 288 |
| rs780873643 | nsSNPs | T /G | 2 | 1175 | Val [V]/Gly [G] | 289 |
| rs775691314 | nsSNPs | C /G | 2 | 1178 | Ser [S]/Cys [C] | 290 |
| rs772619265 | nsSNPs | A /G | 1 | 1180 | Ile [I]/Val [V] | 291 |
| rs760061096 | nsSNPs | T /A | 2 | 1181 | Ile [I]/Lys [K] | 291 |
| rs749789723 | inframe insertion/stop gained | TTT | 2 | 1181 | Leu [L] | 291 |
| rs1205719797 | nsSNPs | T /A | 2 | 1190 | Leu [L]/His [H] | 294 |
| rs1364855365 | nsSNPs | C /G | 2 | 1196 | Thr [T]/Ser [S] | 296 |
| rs368432491 | nsSNPs | A /G | 2 | 1199 | Asn [N]/Ser [S] | 297 |
| rs182778895 | nsSNPs | T /C | 1 | 1201 | Ser [S]/Pro [P] | 298 |
| rs777540740 | nsSNPs | A /T | 1 | 1204 | Ser [S]/Cys [C] | 299 |
| rs769325995 | nsSNPs | T /C | 1 | 1207 | Tyr [Y]/His [H] | 300 |
| rs121909743 | nonsense | C /T | 1 | 1210 | Arg [R]/ | 301 |
| rs374492763 | nsSNPs | G /A | 2 | 1211 | Arg [R]/Gln [Q] | 301 |
| rs374492763 | nsSNPs | G /T | 2 | 1211 | Arg [R]/Leu [L] | 301 |
| rs1326032349 | frame shift | -/TTGG | 3 | 1212 | Gln [Q]/Leu [L] | 302 |
| rs1316522125 | frame shift | C /- | 2 | 1217 | Pro [P]/Leu [L] | 303 |
| rs938526894 | nsSNPs | T /C | 2 | 1223 | Leu [L]/Pro [P] | 305 |
| rs1312418962 | nsSNPs | T /C | 2 | 1235 | Met [M]/Thr [T] | 309 |
| rs1421580115 | nsSNPs | G /A | 1 | 1243 | Val [V]/Met [M] | 312 |
| rs1324205444 | nsSNPs | G /A | 1 | 1246 | Ala [A]/Thr [T] | 313 |
| rs1324205444 | nsSNPs | G /T | 1 | 1246 | Ala [A]/Ser [S] | 313 |
| rs780067980 | nsSNPs | G /A | 1 | 1261 | Gly [G]/Arg [R] | 318 |
| rs369101584 | nsSNPs | A /G | 2 | 1268 | Asn [N]/Ser [S] | 320 |
| rs757366672 | nsSNPs | G /T | 1 | 1270 | Gly [G]/Cys [C] | 321 |
| rs767670296 | nsSNPs | T /A | 2 | 1274 | Ile [I]/Asn [N] | 322 |
| rs1272816101 | nsSNPs | T /G | 3 | 1275 | Ile [I]/Met [M] | 322 |
| rs759952425 | nsSNPs | T /C | 1 | 1282 | Tyr [Y]/His [H] | 325 |
| rs751917665 | nsSNPs | C /T | 2 | 1304 | Thr [T]/Met [M] | 332 |
| rs1441375275 | nsSNPs | G /A | 1 | 1306 | Ala [A]/Thr [T] | 333 |
| rs763345848 | nsSNPs | G /A | 2 | 1310 | Gly [G]/Asp [D] | 334 |
| rs748296868 | frame shift | G /- | 2 | 1310 | Gly [G]/Val [V] | 334 |
| rs1461795294 | nsSNPs | A /G | 1 | 1315 | Ser [S]/Gly [G] | 336 |
| rs773717998 | nsSNPs | C /A | 2 | 1334 | Thr [T]/Asn [N] | 342 |
| rs1162318193 | nsSNPs | T /C | 2 | 1337 | Ile [I]/Thr [T] | 343 |
| rs1050103029 | nsSNPs | T /C | 2 | 1343 | Val [V]/Ala [A] | 345 |
| rs764683908 | nsSNPs | G /A | 2 | 1346 | Gly [G]/Asp [D] | 346 |
| rs776435170 | nsSNPs | G /A | 1 | 1348 | Ala [A]/Thr [T] | 347 |
| rs1236921754 | nsSNPs | C /T | 2 | 1349 | Ala [A]/Val [V] | 347 |
| rs746863503 | nsSNPs | T /G | 2 | 1358 | Met [M]/Arg [R] | 350 |
| rs775407568 | nsSNPs | G /C | 3 | 1359 | Met [M]/Ile [I] | 350 |
| rs771855037 | nsSNPs | G /A | 1 | 1369 | Ala [A]/Thr [T] | 354 |
| rs140815551 | nsSNPs | G /A | 1 | 1372 | Val [V]/Ile [I] | 355 |
| rs1348497054 | nsSNPs | C /G | 2 | 1376 | Ser [S]/Cys [C] | 356 |
| rs1469035471 | nsSNPs | G /C | 1 | 1378 | Val [V]/Leu [L] | 357 |
| rs372845210 | nsSNPs | C /A | 1 | 1384 | Leu [L]/Ile [I] | 359 |
| rs372845210 | nsSNPs | C /T | 1 | 1384 | Leu [L]/Phe [F] | 359 |
| rs1380054283 | nsSNPs | G /C | 1 | 1390 | Glu [E]/Gln [Q] | 361 |
| rs999185720 | nsSNPs | G /T | 3 | 1392 | Glu [E]/Asp [D] | 361 |
| rs745619267 | nsSNPs | G /C | 3 | 1395 | Lys [K]/Asn [N] | 362 |
| rs76362149 | nsSNPs | G /T | 1 | 1396 | Ala [A]/Ser [S] | 363 |
| rs121909742 | nonsense | C /T | 1 | 1402 | Arg [R]/ | 365 |
| rs34066960 | frame shift | -/C | 3 | 1401 | Arg [R]/Pro [P] | 365 |
| rs781225543 | nsSNPs | G /A | 2 | 1403 | Arg [R]/Gln [Q] | 365 |
| rs1321655963 | nsSNPs | C /T | 1 | 1405 | Arg [R]/Cys [C] | 366 |
| rs755000812 | nsSNPs | G /A | 2 | 1406 | Arg [R]/His [H] | 366 |
| rs1174349159 | frame shift | CT /- | 3 | 1413 | Phe [F]/Ser [S] | 369 |
| rs1223071449 | nsSNPs | T /A | 3 | 1416 | Phe [F]/Leu [L] | 369 |
| rs1430684701 | nsSNPs | T /C | 2 | 1418 | Leu [L]/Pro [P] | 370 |
| rs747262541 | nsSNPs | G /A | 2 | 1430 | Ser [S]/Asn [N] | 374 |
| rs868182136 | nsSNPs | G /A | 2 | 1433 | Gly [G]/Glu [E] | 375 |
| rs780255530 | nsSNPs | A /G | 1 | 1435 | Met [M]/Val [V] | 376 |
| rs758699271 | nsSNPs | G /A | 3 | 1437 | Met [M]/Ile [I] | 376 |
| rs946622803 | nsSNPs | T /C | 1 | 1438 | Phe [F]/Leu [L] | 377 |
| rs1381085405 | nsSNPs | T /A | 2 | 1439 | Phe [F]/Tyr [Y] | 377 |
| rs1381085405 | nsSNPs | T /C | 2 | 1439 | Phe [F]/Ser [S] | 377 |
| rs1384674663 | frame shift | TTGT /- | 3 | 1443 | Cys [C]/Pro [P] | 379 |
| rs750782646 | nsSNPs | T /A | 2 | 1451 | Ile [I]/Asn [N] | 381 |
| rs765728439 | nsSNPs | T /C | 2 | 1457 | Met [M]/Thr [T] | 383 |
| rs757805176 | nsSNPs | G /A | 1 | 1465 | Gly [G]/Arg [R] | 386 |
| rs757805176 | nsSNPs | G /C | 1 | 1465 | Gly [G]/Arg [R] | 386 |
| rs1199637811 | nsSNPs | T /G | 2 | 1472 | Val [V]/Gly [G] | 388 |
| rs121909747 | nsSNPs | T /G | 2 | 1475 | Leu [L]/Arg [R] | 389 |
| rs 121,909,747 | nsSNPs | T/C | 2 | 1475 | L (Leu) > P (Pro) | 389 |
| rs760200790 | nsSNPs | T /G | 2 | 1478 | Leu [L]/Arg [R] | 390 |
| rs766191732 | nsSNPs | C /A | 3 | 1488 | Phe [F]/Leu [L] | 393 |
| rs1464417991 | nsSNPs | T /C | 1 | 1489 | Ser [S]/Pro [P] | 394 |
| rs762668792 | nsSNPs | T /A | 2 | 1505 | Val [V]/Glu [E] | 399 |
| rs1457657980 | nsSNPs | A /G | 1 | 1510 | Met [M]/Val [V] | 401 |
| rs374702599 | nsSNPs | T /C | 2 | 1514 | Ile [I]/Thr [T] | 402 |
| rs1161394690 | inframe insertion | GAT | 2 | 1514 | Met [M]/ MetMet [MM] | 401 |
| rs1419532672 | nsSNPs | A /G | 1 | 1519 | Ile [I]/Val [V] | 404 |
| rs2229608 | nsSNPs | T /C | 2 | 1520 | Ile [I]/Thr [T] | 404 |
| rs760729620 | nsSNPs | T /C | 2 | 1529 | Phe [F]/Ser [S] | 407 |
| rs140791627 | nsSNPs | A /T | 1 | 1534 | Ser [S]/Cys [C] | 409 |
| rs746136121 | nsSNPs | T /C | 1 | 1537 | Phe [F]/Leu [L] | 410 |
| rs1353890919 | nsSNPs | T /G | 2 | 1541 | Phe [F]/Cys [C] | 411 |
| rs966424064 | nsSNPs | T/ C | 2 | 1547 | Ile [I]/Thr [T] | 413 |
| rs779212294 | nsSNPs | T /G | 3 | 1548 | Ile [I]/Met [M] | 413 |
| rs121909744 | nsSNPs | C /G | 2 | 1559 | Pro [P]/Arg [R] | 417 |
| rs121909744 | nsSNPs | C /T | 2 | 1559 | Pro [P]/Leu [L] | 417 |
| rs1309197020 | nsSNPs | C /G | 3 | 1563 | Ile [I]/Met [M] | 418 |
| rs1309197020 | nsSNPs | C/A | 3 | 1563 | Ile [I] / Ile [I] | 418 |
| rs121909745 | nonsense | G /A | 2 | 1568 | Trp [W]/ | 420 |
| rs749661374 | nsSNPs | A /G | 1 | 1573 | Met [M]/Val [V] | 422 |
| rs778490867 | nsSNPs | T /C | 2 | 1574 | Met [M]/Thr [T] | 422 |
| rs28928874 | nsSNPs | T /A | 2 | 1577 | Val [V]/Glu [E] | 423 |
| rs1386374799 | frame shift | T /- | 2 | 1589 | Phe [F]/Ser [S] | 427 |
| rs367980651 | nsSNPs | C /T | 1 | 1603 | Arg [R]/Cys [C] | 432 |
| rs75144723 | nsSNPs | G /A | 2 | 1604 | Arg [R]/His [H] | 432 |
| rs754405476 | nsSNPs | G /A | 1 | 1612 | Ala [A]/Thr [T] | 435 |
| rs1379813904 | nsSNPs | C /A | 2 | 1619 | Ala [A]/Glu [E] | 437 |
| rs751226875 | nsSNPs | T /C | 2 | 1622 | Ile [I]/Thr [T] | 438 |
| rs762675284 | nsSNPs | G /T | 1 | 1624 | Ala [A]/Ser [S] | 439 |
| rs1262058831 | nsSNPs | C /T | 2 | 1625 | Ala [A]/Val [V] | 439 |
| rs758246412 | nsSNPs | C /A | 2 | 1628 | Ala [A]/Glu [E] | 440 |
| rs1203908311 | nsSNPs | A /G | 2 | 1637 | Asn [N]/Ser [S] | 443 |
| rs765196886 | nsSNPs | A /C | 1 | 1654 | Ile [I]/Leu [L] | 449 |
| rs761784655 | nsSNPs | T /C | 2 | 1655 | Ile [I]/Thr [T] | 449 |
| rs776395971 | nsSNPs | T /C | 2 | 1658 | Val [V]/Ala [A] | 450 |
| rs1238600269 | nsSNPs | G /A | 1 | 1660 | Ala [A]/Thr [T] | 451 |
| rs1418589512 | nsSNPs | T /C | 1 | 1666 | Cys [C]/Arg [R] | 453 |
| rs1350704340 | frame shift | -/G | 3 | 1665 | Cys [C]/Val [V] | 453 |
| rs759480075 | nsSNPs | T /C | 1 | 1675 | Tyr [Y]/His [H] | 456 |
| rs771274850 | nsSNPs | T /C | 2 | 1679 | Ile [I]/Thr [T] | 457 |
| rs749710583 | nsSNPs | C /A | 2 | 1682 | Ala [A]/Glu [E] | 458 |
| rs749710583 | nsSNPs | C /T | 2 | 1682 | Ala [A]/Val [V] | 458 |
| rs1290975016 | frame shift | -/T | 2 | 1688 | Cys [C]/Leu [L] | 461 |
| rs774542648 | nsSNPs | G /A | 1 | 1693 | Gly [G]/Arg [R] | 462 |
| rs765132996 | frame shift | G /- | 2 | 1694 | Gly [G]/Asp [D] | 462 |
| rs1272353608 | nsSNPs | C /A | 2 | 1697 | Pro [P]/His [H] | 463 |
| rs1381049817 | nsSNPs | A /G | 2 | 1700 | Tyr [Y]/Cys [C] | 464 |
| rs1336322605 | nsSNPs | T /C | 1 | 1708 | Phe [F]/Leu [L] | 467 |
| rs140138702 | nsSNPs | C /G | 1 | 1711 | Leu [L]/Val [V] | 468 |
| rs770197371 | nsSNPs | T /G | 2 | 1712 | Leu [L]/Arg [R] | 468 |
| rs748401954 | nsSNPs | T /C | 2 | 1715 | Phe [F]/Ser [S] | 469 |
| rs1290412048 | frame shift | TT /- | 2 | 1715 | Phe [F]/Cys [C] | 469 |
| rs374342938 | nsSNPs | G /C | 2 | 1721 | Gly [G]/Ala [A] | 471 |
| rs769037887 | nsSNPs | G /A | 1 | 1723 | Val [V]/Met [M] | 472 |
| rs556023421 | nsSNPs | T /C | 1 | 1735 | Phe [F]/Leu [L] | 476 |
| rs5397 | nsSNPs | C /G | 1 | 1741 | Leu [L]/Val [V] | 478 |
| rs5398 | nsSNPs | C /A | 3 | 1746 | Phe [F]/Leu [L] | 479 |
| rs757137603 | nsSNPs | C /T | 2 | 1748 | Thr [T]/Ile [I] | 480 |
| rs1441249949 | nsSNPs | T /A | 1 | 1750 | Phe [F]/ Ile [I] | 481 |
| rs1195253424 | nsSNPs | G /A | 1 | 1759 | Val [V]/Ile [I] | 484 |
| rs753575081 | nsSNPs | C /A | 1 | 1762 | Pro [P]/Thr [T] | 485 |
| rs777806589 | nsSNPs | A /G | 2 | 1772 | Lys [K]/Arg [R] | 488 |
| rs766600474 | nsSNPs | T /A | 1 | 1780 | Ser [S]/Thr [T] | 491 |
| rs766600474 | nsSNPs | T /G | 1 | 1780 | Ser [S]/Ala [A] | 491 |
| rs1379944645 | nonsense | G /T | 1 | 1786 | Glu [E]/ | 493 |
| rs1379944645 | nsSNPs | G /A | 1 | 1786 | Glu [E]/Lys [K] | 493 |
| rs1353603250 | nsSNPs | G /C | 1 | 1789 | Glu [E]/Gln [Q] | 494 |
| rs1446857276 | nsSNPs | A /T | 3 | 1791 | Glu [E]/Asp [D] | 494 |
| rs1283734332 | nsSNPs | T /C | 2 | 1793 | Ile [I]/Thr [T] | 495 |
| rs1445660295 | nsSNPs | C /T | 2 | 1796 | Ala [A]/Val [V] | 496 |
| rs201797691 | nsSNPs | G /A | 1 | 1798 | Ala [A]/Thr [T] | 497 |
| rs201797691 | nsSNPs | G /C | 1 | 1798 | Ala [A]/Pro [P] | 497 |
| rs200160167 | nsSNPs | C /A | 2 | 1799 | Ala [A]/Glu [E] | 497 |
| rs200160167 | nsSNPs | C /T | 2 | 1799 | Ala [A]/Val [V] | 497 |
| rs762305192 | nsSNPs | T /C | 1 | 1804 | Phe [F]/Leu [L] | 499 |
| rs776826621 | nsSNPs | G /C | 3 | 1812 | Lys [K]/Asn [N] | 501 |
| rs5399 | nsSNPs | G /C | 3 | 1815 | Lys [K]/Asn [N] | 502 |
| rs1412427073 | nsSNPs | G /A | 1 | 1819 | Gly [G]/Ser [S] | 504 |
| rs966895511 | nsSNPs | G /T | 1 | 1825 | Ala [A]/Ser [S] | 506 |
| rs1199349184 | nsSNPs | C /T | 2 | 1826 | Ala [A]/Val [V] | 506 |
| rs374630641 | nsSNPs | G /C | 3 | 1833 | Arg [R]/Ser [S] | 508 |
| rs771586150 | nsSNPs | C /A | 2 | 1835 | Pro [P]/Gln [Q] | 509 |
| rs776597156 | nsSNPs | A /C | 3 | 1839 | Lys [K]/Asn[N] | 510 |
| rs770462591 | nsSNPs | C /A | 2 | 1841 | Ala [A]/Asp [D] | 511 |
| rs770462591 | nsSNPs | C /T | 2 | 1841 | Ala [A]/Val [V] | 511 |
| rs141574520 | nsSNPs | T /A | 2 | 1859 | Phe [F]/Tyr [Y] | 517 |
| rs147959014 | nsSNPs | G /A | 2 | 1865 | Gly [G]/Glu [E] | 519 |
| rs752687355 | nsSNPs | A /G | 2 | 1874 | Glu [E]/Gly[G] | 522 |
| rs781215842 | nsSNPs | A /T | 1 | 1876 | Thr [T]/Ser [S] | 523 |
| rs758607933 | nsSNPs | G/ A | 1 | 1879 | Val[V]/Met[M] | 524 |
| rs750463981 | stop lost | T /C | 1 | 1882 | (Ter) /Gln[Q] | 525 |
3.4 Analysis of nsSNPS using SIFT
SIFT forecasts whether amino acid substitution in protein has phenotypic effect or not. Alignment also gave forecasted changes of all amino acid locations. The SIFT intolerance index starting point was 0.05. The color code of non polar, basic, uncharged polar and acidic amino acids were shown by black, red, green and blue color respectively. On the other hand, the amino acid alignment is shown by capital letter while the results of prediction are shown by small letter. 'Seq Rep' was the proportion of sequences that has one of the important amino acids. The position either severely gapped or unalignable was determined by low fraction and it has little information which has poor prediction. Its prediction score ranges from 0 to 1. On phenotypic substitution by aligning orthologous and paralogous protein sequence, this study mainly considers the physical properties of amino acids, effect of natural nsSNPs and alignment of homologous sequences (Noreen et al., 2015a, 2015b). For positions 1–524 of amino acids, the prediction of possible substitutions was made (Figure 6). It was used to predict damaging and tolerated effect of 293 nsSNPs that occurs in coding region of GLUT2 protein. As a consequence, 167 were predicted to be damaging (Table 2).
| dbSNP id | Proteinresidue | SIFT score | SIFTprediction | PolyPhenscore | PolyPhenprediction | PROVEANscore | PROVEAN prediction |
|---|---|---|---|---|---|---|---|
| rs759495940 | Met [M]/Ile [I] | 0.02 | Intolerant | 0.016 | Benign | −1.576 | Neutral |
| rs773205789 | Thr [T]/Pro [P] | 0.08 | Tolerant | 0.003 | Benign | −0.251 | Neutral |
| rs200073044 | Asp [D]/His [H] | 0.16 | Tolerant | 0.001 | Benign | −1.256 | Neutral |
| rs1372689853 | Lys [K]/Glu [E] | 0.27 | Tolerant | 0.009 | Benign | −1.503 | Neutral |
| rs767313610 | Val [V]/Ile [I] | 0.24 | Tolerant | 0.003 | Benign | 0.189 | Neutral |
| rs369700669 | Thr [T]/Asn [N] | 0.05 | Tolerant | 0.505 | Possibly damaging | −4.345 | Deleterious |
| rs1481905618 | Phe [F]/Leu [L] | 1 | Tolerant | 0.002 | Benign | −1.974 | Neutral |
| rs1247912820 | Thr [T]/Asn [N] | 0 | Intolerant | 0.255 | Benign | −1.769 | Neutral |
| rs1247912820 | Thr [T]/Ser [S] | 0.37 | Tolerant | 0.007 | Benign | 0.439 | Neutral |
| rs372441014 | Val [V]/Leu [L] | 0.04 | Intolerant | 0.534 | Possibly damaging | −2.404 | Neutral |
| rs766364438 | Ile [I]/Thr [T] | 0.48 | Tolerant | 0.007 | Benign | −0.108 | Neutral |
| rs1463507753 | I (Ile) > II (IleIle) | – | – | – | – | – | – |
| rs867315854 | Ala [A]/Thr [T] | 0 | Intolerant | 0.951 | Probably damaging | −3.332 | Deleterious |
| rs761992056 | Gly [G]/Asp [D] | 0 | Intolerant | 0.967 | Probably damaging | −5.211 | Deleterious |
| rs369781481 | Phe [F]/Leu [L] | 1 | Tolerant | 0.253 | Benign | −0.832 | Neutral |
| rs1409436045 | Phe [F]/Tyr [Y] | 0.08 | Tolerant | 0.582 | Possibly damaging | −1.774 | Neutral |
| rs1049223265 | Ile [I]/Thr [T] | 0.61 | Tolerant | 0.041 | Benign | −0.47 | Neutral |
| rs1437312005 | Gly [G]/Ser [S] | 0 | Intolerant | 0.996 | Probably damaging | −5.242 | Deleterious |
| rs1437312005 | Gly [G]/Arg [R] | 0 | Intolerant | 1 | Probably damaging | −6.99 | Deleterious |
| rs775531825 | Asn [N]/Ser [S] | 0 | Intolerant | 0.979 | Probably damaging | −4.384 | Deleterious |
| rs143528640 | Ala [A]/Thr [T] | 0.05 | Tolerant | 0.934 | Probably damaging | −3.505 | Deleterious |
| rs746158263 | Pro [P]/Thr [T] | 0 | Intolerant | 0.999 | Probably damaging | −7.021 | Deleterious |
| rs1158195535 | Gln [Q]/Lys [K] | 1 | Tolerant | 0.004 | Benign | 0.622 | Neutral |
| rs1158195535 | Gln [Q]/Glu [E] | 0.14 | Tolerant | 0.002 | Benign | −0.245 | Neutral |
| rs1451394300 | Val [V]/Ile [I] | 0.59 | Tolerant | 0.006 | Benign | −0.067 | Neutral |
| rs1477523180 | Ile [I]/Leu [L] | 0.16 | Tolerant | 0.437 | Benign | −1.338 | Neutral |
| rs1360464436 | Ile [I]/Lys [K] | 0 | Intolerant | 0.977 | Probably damaging | −4.893 | Deleterious |
| rs1176350402 | Ile [I]/Thr [T] | 0.02 | Intolerant | 0.012 | Benign | 0.3 | Neutral |
| rs772999215 | II (IleIle) > I (Ile) | – | – | – | – | −4.083 | Deleterious |
| rs758670698 | Arg [R]/Ile [I] | 0.14 | Tolerant | 0.016 | Benign | −2.042 | Neutral |
| rs760618624 | His [H]/Tyr [Y] | 0.04 | Intolerant | 0 | Benign | −1.705 | Neutral |
| rs775791143 | Val [V]/Ile [I] | 0.09 | Tolerant | 0.098 | Benign | −0.283 | Neutral |
| rs149108283 | Val [V]/Asp [D] | 0.02 | Intolerant | 0.689 | Possibly damaging | −2.294 | Neutral |
| rs149108283 | Val [V]/Ala [A] | 0.14 | Tolerant | 0.034 | Benign | −1.116 | Neutral |
| rs1159338702 | Gly [G]/Ser [S] | 0.01 | Intolerant | 0.653 | Possibly damaging | −1.878 | Neutral |
| rs561765982 | Val [V]/Ile [I] | 0.11 | Tolerant | 0.006 | Benign | −0.204 | Neutral |
| rs983907950 | Pro [P]/Ser [S] | 0.41 | Tolerant | 0.004 | Benign | −1.397 | Neutral |
| rs1211075508 | Leu [L]/Pro [P] | 0.32 | Tolerant | 0.01 | Benign | −1.458 | Neutral |
| rs1311902495 | Asp [D]/Asn[N] | 0.34 | Tolerant | 0.493 | Possibly damaging | −0.762 | Neutral |
| rs1311902495 | Asp [D]/Tyr [Y] | 0.01 | Intolerant | 0.873 | Possibly damaging | −2.194 | Neutral |
| rs771477447 | Arg [R]/Gly [G] | 0.05 | Tolerant | 0.013 | Benign | −1.477 | Neutral |
| rs145210664 | Arg [R]/Gln [Q] | 0.18 | Tolerant | 0.039 | Benign | −0.58 | Neutral |
| rs546539032 | Lys [K]/Asn [N] | 0.48 | Tolerant | 0.038 | Benign | −0.733 | Neutral |
| rs747555903 | Val [V]/Ile [I] | 0.43 | Tolerant | 0.006 | Benign | −0.048 | Neutral |
| rs977284195 | Ile [I]/Thr [T] | 0.65 | Tolerant | 0.003 | Benign | −0.17 | Neutral |
| rs780903829 | Ile [I]/Met [M] | 0.17 | Tolerant | 0.006 | Benign | −0.304 | Neutral |
| rs1169887677 | INS (IleAsnSer) > () | – | – | – | – | – | – |
| rs1373290524 | Ser [S]/Thr [T] | 0.61 | Tolerant | 0.005 | Benign | −0.656 | Neutral |
| rs1310901426 | Thr [T]/Ala [A] | 0.78 | Tolerant | 0.484 | Possibly damaging | −1.49 | Neutral |
| rs1354126805 | Thr [T]/Arg [R] | 0.53 | Tolerant | 0.93 | Probably damaging | −1.61 | Neutral |
| rs754585542 | Asp [D]/Asn[N] | 0.6 | Tolerant | 0.003 | Benign | −0.514 | Neutral |
| rs1217666649 | Asp [D]/Glu [E] | 1 | Tolerant | 0.001 | Benign | −0.257 | Neutral |
| rs1391257598 | Pro [P]/Thr [T] | 0.01 | Intolerant | 0.005 | Benign | −0.821 | Neutral |
| rs7637863 | Pro [P]/Leu [L] | 0.05 | Intolerant | 0.005 | Benign | −0.881 | Neutral |
| rs779977931 | Thr [T]/Lys [K] | 0.16 | Tolerant | 0.037 | Benign | −0.951 | Neutral |
| rs1182852354 | Ile [I]/Val [V] | 0.67 | Tolerant | 0.001 | Benign | 0.053 | Neutral |
| rs750405382 | Met [M]/Val[V] | 0.6 | Tolerant | 0.001 | Benign | 0.191 | Neutral |
| rs1207297111 | Asn [N]/Asp[D] | 0.84 | Tolerant | 0.001 | Benign | −0.029 | Neutral |
| rs1342979475 | Asn [N]/Thr [T] | 0.69 | Tolerant | 0 | Benign | 0.053 | Neutral |
| rs1274084408 | Pro [P]/Ala [A] | 0.73 | Tolerant | 0.01 | Benign | −0.158 | Neutral |
| rs778655073 | Pro [P]/Leu [L] | 0.01 | Intolerant | 0.258 | Benign | −1.466 | Neutral |
| rs549263048 | Trp [W]/Arg [R] | 0.07 | Tolerant | 0 | Benign | −1.382 | Neutral |
| rs531049536 | Trp [W]/Cys [C] | 0.03 | Intolerant | 0.069 | Benign | −1.624 | Neutral |
| rs150851401 | Glu [E]/Lys [K] | 0.03 | Intolerant | 0.004 | Benign | −0.777 | Neutral |
| rs766762468 | Thr [T]/Ser [S] | 0.71 | Tolerant | 0.004 | Benign | −0.271 | Neutral |
| rs766762468 | Thr (T)/ Ile (I) | 0.18 | Tolerant | 0.039 | Benign | −0.862 | Neutral |
| rs763255363 | Ala [A]/Ser [S] | 0.74 | Tolerant | 0.016 | Benign | 0.281 | Neutral |
| rs144715667 | Ile [I]/Val [V] | 0.53 | Tolerant | 0.002 | Benign | −0.043 | Neutral |
| rs1415169647 | Met [M]/Arg[R] | 0.07 | Tolerant | 0.179 | Benign | −2.363 | Neutral |
| rs1407375423 | Trp [W]/Cys [C] | 0 | Intolerant | 0.999 | Probably damaging | −11.435 | Deleterious |
| rs1800572 | Val [V]/Ile [I] | 0 | Intolerant | 0.997 | Probably damaging | −0.887 | Neutral |
| rs1800572 | Val [V] / Leu[L] | 0 | Intolerant | 0.996 | Probably damaging | −2.66 | Deleterious |
| rs770135219 | Val [V]/Ala [A] | 0 | Intolerant | 0.991 | Probably damaging | −3.541 | Deleterious |
| rs1399091893 | Ala [A]/Val [V] | 0 | Intolerant | 0.542 | Possibly damaging | −2.559 | Deleterious |
| rs1332764085 | Val [V]/Ile [I] | 0.39 | Tolerant | 0.026 | Benign | −0.536 | Neutral |
| rs5400 | Thr [T]/Ile [I] | 1 | Tolerant | 0 | Benign | 3.394 | Neutral |
| rs377238940 | Ala [A]/Pro [P] | 0.01 | Intolerant | 0.808 | Possibly damaging | −2.114 | Neutral |
| rs768407637 | Gly [G]/Val [V] | 0 | Intolerant | 0.996 | Probably damaging | −6.815 | Deleterious |
| rs753980727 | Trp [W]/Cys [C] | 0.01 | Intolerant | 0.704 | Possibly damaging | −2.72 | Deleterious |
| rs746632604 | Gly [G]/Ala [A] | 1 | Tolerant | 0.011 | Benign | −0.025 | Neutral |
| rs772002572 | Thr [T]/Ile [I] | 0.02 | Intolerant | 0.003 | Benign | −1.408 | Neutral |
| rs1476520648 | Ile [I]/Asn [N] | 0.09 | Tolerant | 0.18 | Benign | −0.471 | Neutral |
| rs760201098 | Ala [A]/Asp [D] | 0.03 | Intolerant | 0.616 | Possibly damaging | −2.467 | Neutral |
| rs1267904495 | Met [M]/Thr [T] | 0 | Intolerant | 0.799 | Possibly damaging | −5.134 | Deleterious |
| rs1212980167 | Met [M]/Ile [I] | 0 | Intolerant | 0.175 | Benign | −3.41 | Deleterious |
| rs367856967 | Val [V]/Ala [A] | 0.27 | Tolerant | 0.004 | Benign | −1.196 | Neutral |
| rs970550665 | Ala [A]/Gly [G] | 0.53 | Tolerant | 0.526 | Possibly damaging | −1.704 | Neutral |
| rs775283150 | Ile [I]/Phe [F] | 0.05 | Tolerant | 0.082 | Benign | −2.379 | Neutral |
| rs913419413 | Leu [L]/Arg [R] | 0 | Intolerant | 0.954 | Probably damaging | −4.778 | Deleterious |
| rs771843187 | Ser [S]/Pro [P] | 0 | Intolerant | 0.82 | Possibly damaging | −2.268 | Neutral |
| rs144125084 | Val [V]/Leu [L] | 0.75 | Tolerant | 0.006 | Benign | −0.509 | Neutral |
| rs993833041 | Val [V]/Ala [A] | 0.6 | Tolerant | 0.004 | Benign | −1.391 | Neutral |
| rs1300072764 | Gly [G]/Glu [E] | 0 | Intolerant | 0.991 | Probably damaging | −5.45 | Deleterious |
| rs778548964 | Leu [L]/Phe [F] | 0.65 | Tolerant | 0.125 | Benign | −1.799 | Neutral |
| rs1016384738 | Met [M]/Lys[K] | 0 | Intolerant | 0.979 | Probably damaging | −5.027 | Deleterious |
| rs770941010 | Gly [G]/Arg [R] | 0 | Intolerant | 0.89 | Possibly damaging | −5.634 | Deleterious |
| rs777718289 | Gly [G]/Glu [E] | 0.02 | Intolerant | 0.588 | Possibly damaging | −3.269 | Deleterious |
| rs777718289 | Gly [G]/Val [V] | 0.04 | Intolerant | 0.065 | Benign | −3.177 | Deleterious |
| rs372621339 | Pro [P]/Arg [R] | 0.54 | Tolerant | 0.017 | Benign | −0.696 | Neutral |
| rs747025551 | Ile [I]/Thr [T] | 0.14 | Tolerant | 0.158 | Benign | 0.37 | Neutral |
| rs376064965 | Leu [L]/Phe [F] | 0 | Intolerant | 0.114 | Benign | −2.421 | Neutral |
| rs763620441 | ILI (IleLeuIle) /I(Ile) | – | – | – | – | – | – |
| rs1188886679 | Ile [I]/Leu [L] | 1 | Tolerant | 0.006 | Benign | −0.029 | Neutral |
| rs1188886679 | Ile [I]/Val [V] | 0.28 | Tolerant | 0.02 | Benign | −0.518 | Neutral |
| rs192720796 | Ile [I]/Lys [K] | 0 | Intolerant | 0.616 | Possibly damaging | −4.296 | Deleterious |
| rs910976682 | Ala [A]/Val [V] | 0.24 | Tolerant | 0.007 | Benign | 0.447 | Neutral |
| rs750836049 | Gly [G]/Arg [R] | 0 | Intolerant | 0.996 | Probably damaging | −7.236 | Deleterious |
| rs1278964539 | Arg [R]/Lys [K] | 0 | Intolerant | 0.999 | Probably damaging | −2.714 | Deleterious |
| rs1231468128 | Leu [L]/Gln [Q] | 0 | Intolerant | 0.951 | Probably damaging | −4.187 | Deleterious |
| rs1445887606 | Tyr [Y]/His [H] | 0.08 | Tolerant | 0.319 | Benign | −3.492 | Deleterious |
| rs1271546287 | Ile [I]/Thr [T] | 1 | Tolerant | 0.007 | Benign | 0.249 | Neutral |
| rs760095835 | Gly [G]/Asp [D] | 0 | Intolerant | 0.998 | Probably damaging | −6.71 | Deleterious |
| rs1335888503 | Val [V]/Leu [L] | 0 | Intolerant | 0.48 | Possibly damaging | −2.654 | Deleterious |
| rs1293130515 | Met [M]/Thr [T] | 0 | Intolerant | 0.792 | Possibly damaging | −5.465 | Deleterious |
| rs1019696977 | Ile [I]/Val [V] | 1 | Tolerant | 0.014 | Benign | −0.016 | Neutral |
| rs144822218 | Gly [G]/Ser [S] | 0.19 | Tolerant | 0.153 | Benign | −4.8 | Deleterious |
| rs759047405 | Gly [G]/Asp [D] | 0 | Intolerant | 0.275 | Benign | −6.064 | Deleterious |
| rs1441606652 | Ala [A]/Val [V] | 0 | Intolerant | 0.93 | Probably damaging | −3.261 | Deleterious |
| rs368626129 | Ala [A]/Thr [T] | 0.8 | Tolerant | 0.015 | Benign | −0.903 | Neutral |
| rs368626129 | Ala [A]/Ser [S] | 0.86 | Tolerant | 0.012 | Benign | −0.098 | Neutral |
| rs200213178 | Ala [A]/Thr [T] | 0 | Intolerant | 0.838 | Possibly damaging | −3.928 | Deleterious |
| rs200213178 | Ala [A]/Pro [P] | 0 | Intolerant | 0.996 | Probably damaging | −4.91 | Deleterious |
| rs748052042 | Leu [L]/Phe [F] | 0.31 | Tolerant | 0.044 | Benign | −1.051 | Neutral |
| rs1412289847 | Gly [G]/Ser [S] | 0 | Intolerant | 0.994 | Probably damaging | −5.883 | Deleterious |
| rs776498787 | Gly [G]/Asp [D] | 0 | Intolerant | 0.999 | Probably damaging | −6.867 | Deleterious |
| rs779065938 | Leu [L]/Val [V] | 0.03 | Intolerant | 0.951 | Probably damaging | −2.948 | Deleterious |
| rs1469335096 | Ala [A]/Thr [T] | 0.01 | Intolerant | 0.688 | Possibly damaging | −2.844 | Deleterious |
| rs771182536 | Ile [I]/Asn [N] | 0 | Intolerant | 0.961 | Probably damaging | −6.383 | Deleterious |
| rs771182536 | Ile [I]/Thr [T] | 0.02 | Intolerant | 0.517 | Possibly damaging | −4.26 | Deleterious |
| rs121909741 | Val [V]/Ile [I] | 0.01 | Intolerant | 0.846 | Possibly damaging | −0.978 | Neutral |
| rs149460434 | Thr [T]/Lys [K] | 0 | Intolerant | 0.665 | Possibly damaging | −3.176 | Deleterious |
| rs149460434 | Thr [T]/Met[M] | 0.01 | Intolerant | 0.166 | Benign | −0.836 | Neutral |
| rs1276756236 | Leu [L]/Ile [I] | 0 | Intolerant | 0.967 | Probably damaging | −1.897 | Neutral |
| rs779591826 | Ile [I]/Met [M] | 0 | Intolerant | 0.973 | Probably damaging | −2.473 | Neutral |
| rs1262860274 | Ile [I]/Thr [T] | 0.01 | Intolerant | 0.102 | Benign | −2.589 | Deleterious |
| rs1186359171 | Gly [G]/Ser [S] | 0 | Intolerant | 0.982 | Probably damaging | −5.869 | Deleterious |
| rs1215469128 | Leu [L]/Ser [S] | 0 | Intolerant | 0.993 | Probably damaging | −4.95 | Deleterious |
| rs1347267249 | Asn [N]/His [H] | 0.01 | Intolerant | 0.413 | Benign | −3.346 | Deleterious |
| rs573292685 | Asn [N]/Ser [S] | 0.88 | Tolerant | 0.048 | Benign | −1.171 | Neutral |
| rs764799427 | Asp [D]/Val [V] | 0.08 | Tolerant | 0.027 | Benign | −3.592 | Deleterious |
| rs1380319602 | Ile [I]/Asn [N] | 0 | Intolerant | 0.863 | Possibly damaging | −5.167 | Deleterious |
| rs760641937 | Gly [G]/Ala [A] | 0.26 | Tolerant | 0.401 | Benign | −3.395 | Deleterious |
| rs1413841367 | Leu [L]/Pro [P] | 0 | Intolerant | 0.996 | Probably damaging | −5.774 | Deleterious |
| rs771075989 | Val [V]/Met [M] | 0.02 | Intolerant | 0.863 | Possibly damaging | −1.251 | Neutral |
| rs773581866 | Arg [R]/Gly [G] | 0 | Intolerant | 0.008 | Benign | −0.341 | Neutral |
| rs770126214 | Leu [L]/Ile [I] | 0.09 | Tolerant | 0.032 | Benign | −1.069 | Neutral |
| rs1374154306 | Leu [L]/Gln [Q] | 0 | Intolerant | 0.853 | Possibly damaging | −4.116 | Deleterious |
| rs748588515 | Leu [L]/Phe [F] | 0 | Intolerant | 0.914 | Probably damaging | −3.922 | Deleterious |
| rs757087261 | Phe [F]/Ile [I] | 0.08 | Tolerant | 0.219 | Benign | −4.242 | Deleterious |
| rs777020657 | Phe [F]/Cys [C] | 0.03 | Intolerant | 0.359 | Benign | −6.281 | Deleterious |
| rs777020657 | F (Phe) > S (Ser) | 0 | Intolerant | 0.936 | Probably damaging | −6.607 | Deleterious |
| rs769089021 | Ser [S]/Asn [N] | 0 | Intolerant | 0.999 | Probably damaging | −2.946 | Deleterious |
| rs780381836 | Arg [R]/Gly [G] | 0.01 | Intolerant | 0.548 | Possibly damaging | −6.565 | Deleterious |
| rs1480881050 | Tyr [Y]/His [H] | 0 | Intolerant | 0.903 | Possibly damaging | −4.446 | Deleterious |
| rs1250722271 | Tyr [Y]/His [H] | 0 | Intolerant | 0.928 | Probably damaging | −3.256 | Deleterious |
| rs1158317020 | Tyr [Y]/Phe [F] | 0.06 | Tolerant | 0.02 | Benign | −1.172 | Neutral |
| rs867996396 | Ile [I]/Asn [N] | 0 | Intolerant | 0.958 | Probably damaging | −6.497 | Deleterious |
| rs867996396 | Ile [I] / Thr [T] | 0 | Intolerant | 0.925 | Probably damaging | −4.799 | Deleterious |
| rs536261161 | Lys [K]/Asn [N] | 1 | Tolerant | 0.004 | Benign | 0.309 | Neutral |
| rs745373269 | Asp [D]/Asn [N] | 1 | Tolerant | 0.003 | Benign | 0.872 | Neutral |
| rs745373269 | Asp [D]/His [H] | 0.05 | Tolerant | 0.637 | Possibly damaging | −1.072 | Neutral |
| rs1367431424 | Glu [E]/Ala [A] | 0.2 | Tolerant | 0.155 | Benign | −3.915 | Deleterious |
| rs865881030 | Glu [E]/Lys [K] | 0 | Intolerant | 0.377 | Benign | −3.096 | Deleterious |
| rs778607566 | Glu [E]/Gly [G] | 0 | Intolerant | 0.944 | Probably damaging | −5.575 | Deleterious |
| rs1309254226 | Glu [E]/Asp [D] | 0.03 | Intolerant | 0.247 | Benign | −2.277 | Neutral |
| rs777225980 | Ser [S]/Arg [R] | 0.07 | Tolerant | 0.689 | Possibly damaging | −2.569 | Deleterious |
| rs76026576 | Leu [L]/Phe [F] | 0 | Intolerant | 0.998 | Probably damaging | −3.757 | Deleterious |
| rs1490504926 | Asp [D]/Asn[N] | 0.51 | Tolerant | 0.005 | Benign | −0.126 | Neutral |
| rs935009475 | Asp [D]/Glu [E] | 0.06 | Tolerant | 0.434 | Benign | −3.438 | Deleterious |
| rs774721090 | DD (AspAsp) / D (Asp) | – | – | – | – | −6.952 | Deleterious |
| rs140285191 | Asp [D]/Asn[N] | 0 | Intolerant | 0.516 | Possibly damaging | −4.047 | Deleterious |
| rs140285191 | Asp [D]/Tyr [Y] | 0 | Intolerant | 0.981 | Probably damaging | −7.312 | Deleterious |
| rs754932741 | Met [M]/Ile [I] | 0 | Intolerant | 0.17 | Benign | −3.506 | Deleterious |
| rs750579210 | Arg [R]/Gly [G] | 0 | Intolerant | 0.579 | Possibly damaging | −4.146 | Deleterious |
| rs1304842107 | Lys [K]/Gln [Q] | 0.07 | Tolerant | 0.166 | Benign | −0.767 | Neutral |
| rs765426962 | Lys [K]/Thr [T] | 0.13 | Tolerant | 0.065 | Benign | −2.692 | Deleterious |
| rs761756532 | Lys [K]/Asn [N] | 0.09 | Tolerant | 0.036 | Benign | −1.633 | Neutral |
| rs1329237779 | Glu [E]/Lys [K] | 1 | Tolerant | 0.03 | Benign | −0.266 | Neutral |
| rs1384542256 | Glu [E]/Ala [A] | 0.64 | Tolerant | 0.055 | Benign | −3.333 | Deleterious |
| rs776912318 | Ser [S]/Arg [R] | 1 | Tolerant | 0.009 | Benign | −0.133 | Neutral |
| rs776912318 | Ser [S]/Cys [C] | 0.02 | Intolerant | 0.031 | Benign | −2.646 | Deleterious |
| rs764161243 | Lys [K]/Thr [T] | 0.05 | Tolerant | 0.133 | Benign | −4.412 | Deleterious |
| rs780873643 | Val [V]/Gly [G] | 0 | Intolerant | 0.943 | Probably damaging | −6.041 | Deleterious |
| rs775691314 | Ser [S]/Cys [C] | 0 | Intolerant | 0.984 | Probably damaging | −3.556 | Deleterious |
| rs772619265 | Ile [I]/Val [V] | 0.4 | Tolerant | 0.02 | Benign | −0.515 | Neutral |
| rs760061096 | Ile [I]/Lys [K] | 0 | Intolerant | 0.824 | Possibly damaging | −5.896 | Deleterious |
| rs749789723 | Leu [L] | – | – | – | – | – | – |
| rs1205719797 | Leu [L]/His [H] | 0 | Intolerant | 0.999 | Probably damaging | −6.482 | Deleterious |
| rs1364855365 | Thr [T]/Ser [S] | 0.58 | Tolerant | 0.065 | Benign | −0.827 | Neutral |
| rs368432491 | Asn [N]/Ser [S] | 1 | Tolerant | 0.006 | Benign | 1.283 | Neutral |
| rs182778895 | Ser [S]/Pro [P] | 1 | Tolerant | 0.004 | Benign | 1.098 | Neutral |
| rs777540740 | Ser [S]/Cys [C] | 0.06 | Tolerant | 0.031 | Benign | −2.516 | Deleterious |
| rs769325995 | Tyr [Y]/His [H] | 0.11 | Tolerant | 0.32 | Benign | −4.3 | Deleterious |
| rs374492763 | Arg [R]/Gln [Q] | 0.04 | Intolerant | 0.771 | Possibly damaging | −3.702 | Deleterious |
| rs374492763 | Arg [R]/Leu [L] | 0 | Intolerant | 0.906 | Possibly damaging | −6.535 | Deleterious |
| rs938526894 | Leu [L]/Pro [P] | 0 | Intolerant | 0.811 | Possibly damaging | −4.885 | Deleterious |
| rs1312418962 | Met [M]/Thr [T] | 0.03 | Intolerant | 0.411 | Benign | −3.131 | Deleterious |
| rs1421580115 | Val [V]/Met [M] | 0.04 | Intolerant | 0.007 | Benign | 0.763 | Neutral |
| rs1324205444 | Ala [A]/Thr [T] | 0 | Intolerant | 0.842 | Possibly damaging | −0.976 | Neutral |
| rs1324205444 | Ala [A]/Ser [S] | 1 | Tolerant | 0.138 | Benign | 1.321 | Neutral |
| rs780067980 | Gly [G]/Arg [R] | 0 | Intolerant | 1 | Probably damaging | −7.439 | Deleterious |
| rs369101584 | Asn [N]/Ser [S] | 0.01 | Intolerant | 0.919 | Probably damaging | −4.649 | Deleterious |
| rs757366672 | Gly [G]/Cys [C] | 0 | Intolerant | 0.507 | Possibly damaging | −2.067 | Neutral |
| rs767670296 | Ile [I]/Asn [N] | 0 | Intolerant | 0.99 | Probably damaging | −6.223 | Deleterious |
| rs1272816101 | Ile [I]/Met [M] | 0 | Intolerant | 0.985 | Probably damaging | −2.411 | Neutral |
| rs759952425 | Tyr [Y]/His [H] | 0 | Intolerant | 0.986 | probaly damaging | −4.763 | Deleterious |
| rs751917665 | Thr [T]/Met [M] | 0.03 | Intolerant | 0.075 | Benign | −2.321 | Neutral |
| rs1441375275 | Ala [A]/Thr [T] | 0 | Intolerant | 0.955 | Probably damaging | −3.749 | Deleterious |
| rs763345848 | Gly [G]/Asp [D] | 0 | Intolerant | 0.96 | Probably damaging | −6.283 | Deleterious |
| rs1461795294 | Ser [S]/Gly [G] | 0.47 | Tolerant | 0.013 | Benign | −1.028 | Neutral |
| rs773717998 | Thr [T]/Asn [N] | 0 | Intolerant | 0.986 | Probably damaging | −4.736 | Deleterious |
| rs1162318193 | Ile [I]/Thr [T] | 0 | Intolerant | 0.775 | Possibly damaging | −4.7 | Deleterious |
| rs1050103029 | Val [V]/Ala [A] | 1 | Tolerant | 0.071 | Benign | 0.25 | Neutral |
| rs764683908 | Gly [G]/Asp [D] | 0 | Intolerant | 1 | Probably damaging | −6.631 | Deleterious |
| rs776435170 | Ala [A]/Thr [T] | 0.02 | Intolerant | 0.032 | Benign | −0.943 | Neutral |
| rs1236921754 | Ala [A]/Val [V] | 1 | Tolerant | 0.006 | Benign | 1.67 | Neutral |
| rs746863503 | Met [M]/Arg[R] | 0 | Intolerant | 0.034 | Benign | −1.288 | Neutral |
| rs775407568 | Met [M]/Ile [I] | 0.06 | Tolerant | 0.001 | Benign | −0.367 | Neutral |
| rs771855037 | Ala [A]/Thr [T] | 0.01 | Intolerant | 0.102 | Benign | −0.618 | Neutral |
| rs140815551 | Val [V]/Ile [I] | 0.03 | Intolerant | 0.047 | Benign | −0.733 | Neutral |
| rs1348497054 | Ser [S]/Cys [C] | 0 | Intolerant | 0.929 | Probably damaging | −4.52 | Deleterious |
| rs1469035471 | Val [V]/Leu [L] | 1 | Tolerant | 0.105 | Benign | 0.367 | Neutral |
| rs372845210 | Leu [L]/Ile [I] | 0.04 | Intolerant | 0.817 | Possibly damaging | −1.156 | Neutral |
| rs372845210 | Leu [L]/Phe [F] | 0 | Intolerant | 0.94 | Probably damaging | −3.045 | Deleterious |
| rs1380054283 | Glu [E]/Gln [Q] | 0 | Intolerant | 0.984 | Probably damaging | −2.416 | Neutral |
| rs999185720 | Glu [E]/Asp [D] | 0.31 | Tolerant | 0.162 | Benign | −2.169 | Neutral |
| rs745619267 | Lys [K]/Asn [N] | 0 | Intolerant | 0.821 | Possibly damaging | −2.418 | Neutral |
| rs76362149 | Ala [A]/Ser [S] | 0 | Intolerant | 0.457 | Possibly damaging | −2.448 | Neutral |
| rs781225543 | Arg [R]/Gln [Q] | 0 | Intolerant | 1 | Probably damaging | −3.368 | Deleterious |
| rs1321655963 | Arg [R]/Cys [C] | 0 | Intolerant | 0.998 | Probably damaging | −6.914 | Deleterious |
| rs755000812 | Arg [R]/His [H] | 0 | Intolerant | 0.996 | Probably damaging | −4.126 | Deleterious |
| rs1223071449 | Phe [F]/Leu [L] | 0.14 | Tolerant | 0.004 | Benign | −2.507 | Deleterious |
| rs1430684701 | Leu [L]/Pro [P] | 0 | Intolerant | 0.988 | Probably damaging | −5.765 | Deleterious |
| rs747262541 | Ser [S]/Asn [N] | 0.01 | Intolerant | 0.361 | Benign | −1.303 | Neutral |
| rs868182136 | Gly [G]/Glu [E] | 0 | Intolerant | 0.99 | Probably damaging | −6.873 | Deleterious |
| rs780255530 | Met [M]/Val [V] | 0 | Intolerant | 0.491 | Possibly damaging | −3.484 | Deleterious |
| rs758699271 | Met [M]/Ile [I] | 0 | Intolerant | 0.612 | Possibly damaging | −3.451 | Deleterious |
| rs946622803 | Phe [F]/Leu [L] | 0.49 | Tolerant | 0.006 | Benign | 0.13 | Neutral |
| rs1381085405 | Phe [F]/Tyr [Y] | 0.23 | Tolerant | 0.652 | Possibly damaging | −0.543 | Neutral |
| rs1381085405 | Phe [F]/Ser [S] | 0.41 | Tolerant | 0.063 | Benign | 0.376 | Neutral |
| rs750782646 | Ile [I]/Asn [N] | 0 | Intolerant | 0.811 | Possibly damaging | −4.874 | Deleterious |
| rs765728439 | Met [M]/Thr [T] | 0 | Intolerant | 0.403 | Benign | −5.185 | Deleterious |
| rs757805176 | Gly [G]/Arg [R] | 0 | Intolerant | 0.752 | Possibly damaging | −2.96 | Deleterious |
| rs757805176 | Gly [G]/Arg [R] | 0 | Intolerant | 0.752 | Possibly damaging | −2.96 | Deleterious |
| rs1199637811 | Val [V]/Gly [G] | 0.19 | Tolerant | 0.027 | Benign | −2.318 | Neutral |
| rs121909747 | Leu [L]/Arg [R] | 0 | Intolerant | 0.947 | Probably damaging | −4.842 | Deleterious |
| rs 121,909,747 | Leu [L] / Pro [P] | 0.01 | Intolerant | 0.618 | Possibly damaging | −5.813 | Deleterious |
| rs760200790 | Leu [L]/Arg [R] | 0.6 | Tolerant | 0.139 | Benign | −1.45 | Neutral |
| rs766191732 | Phe [F]/Leu [L] | 0.69 | Tolerant | 0.002 | Benign | −1.523 | Neutral |
| rs1464417991 | Ser [S]/Pro [P] | 1 | Tolerant | 0.005 | Benign | −0.341 | Neutral |
| rs762668792 | Val [V]/Glu [E] | 0 | Intolerant | 0.866 | Possibly damaging | −5.082 | Deleterious |
| rs1457657980 | Met [M]/Val [V] | 0.27 | Tolerant | 0.03 | Benign | −0.744 | Neutral |
| rs1161394690 | M (Met) > MM(MetMet) | – | – | – | – | – | – |
| rs374702599 | Ile [I]/Thr [T] | 0.18 | Tolerant | 0.002 | Benign | −0.852 | Neutral |
| rs1419532672 | Ile [I]/Val [V] | 0.19 | Tolerant | 0.139 | Benign | −0.555 | Neutral |
| rs2229608 | Ile [I]/Thr [T] | 0.21 | Tolerant | 0.401 | Benign | −3.639 | Deleterious |
| rs760729620 | Phe [F]/Ser [S] | 0 | Intolerant | 0.861 | Possibly damaging | −7.529 | Deleterious |
| rs140791627 | Ser [S]/Cys [C] | 0.05 | Tolerant | 0.082 | Benign | −2.035 | Neutral |
| rs746136121 | Phe [F]/Leu [L] | 0.06 | Tolerant | 0.38 | Benign | −3.987 | Deleterious |
| rs1353890919 | Phe [F]/Cys [C] | 0 | Intolerant | 1 | Probably damaging | −7.57 | Deleterious |
| rs966424064 | Ile [I]/Thr [T] | 0 | Intolerant | 0.206 | Benign | −4.159 | Deleterious |
| rs779212294 | Ile [I]/Met [M] | 0.08 | Tolerant | 0.643 | Possibly damaging | −2.032 | Neutral |
| rs121909744 | Pro [P]/Arg [R] | 0 | Intolerant | 0.998 | Probably damaging | −8.516 | Deleterious |
| rs121909744 | Pro [P]/Leu [L] | 0 | Intolerant | 0.994 | Probably damaging | −9.463 | Deleterious |
| rs1309197020 | Ile [I]/Met [M] | 0 | Intolerant | 1 | Probably damaging | −2.838 | Deleterious |
| rs1309197020 | I (Ile) / I (Ile) | 1 | Tolerant | – | – | 0 | Neutral |
| rs749661374 | Met [M]/Val [V] | 0.01 | Intolerant | 0.004 | Benign | 0.655 | Neutral |
| rs778490867 | Met [M]/Thr [T] | 0 | Intolerant | 0.016 | Benign | −2.558 | Deleterious |
| rs28928874 | Val [V]/Glu [E] | 0 | Intolerant | 0.976 | Probably damaging | −5.619 | Deleterious |
| rs367980651 | Arg [R]/Cys [C] | 0 | Intolerant | 0.983 | Probably damaging | −7.42 | Deleterious |
| rs75144723 | Arg [R]/His [H] | 0 | Intolerant | 0.986 | Probably damaging | −4.632 | Deleterious |
| rs754405476 | Ala [A]/Thr [T] | 0 | Intolerant | 0.992 | Probably damaging | −3.706 | Deleterious |
| rs1379813904 | Ala [A]/Glu [E] | 0 | Intolerant | 0.987 | Probably damaging | −4.592 | Deleterious |
| rs751226875 | Ile [I]/Thr [T] | 0 | Intolerant | 0.678 | Possibly damaging | −3.063 | Deleterious |
| rs762675284 | Ala [A]/Ser [S] | 0.07 | Tolerant | 0.665 | Possibly damaging | −1.839 | Neutral |
| rs1262058831 | Ala [A]/Val [V] | 0 | Intolerant | 0.99 | Probably damaging | −3.433 | Deleterious |
| rs758246412 | Ala [A]/Glu [E] | 0.02 | Intolerant | 0.515 | Possibly damaging | −2.432 | Neutral |
| rs1203908311 | Asn [N]/Ser [S] | 0 | Intolerant | 0.992 | Probably damaging | −4.589 | Deleterious |
| rs765196886 | Ile [I]/Leu [L] | 0.59 | Tolerant | 0.009 | Benign | −0.308 | Neutral |
| rs761784655 | Ile [I]/Thr [T] | 0 | Intolerant | 0.213 | Benign | −3.564 | Deleterious |
| rs776395971 | Val [V]/Ala [A] | 0 | Intolerant | 0.895 | Possibly damaging | −3.625 | Deleterious |
| rs1238600269 | Ala [A]/Thr [T] | 0 | Intolerant | 0.219 | Benign | −2.469 | Neutral |
| rs1418589512 | Cys [C]/Arg [R] | 0.13 | Tolerant | 0.532 | Possibly damaging | −4.842 | Deleterious |
| rs759480075 | Tyr [Y]/His [H] | 0.15 | Tolerant | 0.976 | Probably damaging | −3.381 | Deleterious |
| rs771274850 | Ile [I]/Thr [T] | 0.01 | Intolerant | 0.653 | Possibly damaging | −2.456 | Neutral |
| rs749710583 | Ala [A]/Glu [E] | 0.75 | Tolerant | 0.025 | Benign | −1.512 | Neutral |
| rs749710583 | Ala [A]/Val [V] | 0.18 | Tolerant | 0.025 | Benign | −2.403 | Neutral |
| rs774542648 | Gly [G]/Arg [R] | 0 | Intolerant | 0.734 | Possibly damaging | −7.25 | Deleterious |
| rs1272353608 | Pro [P]/His [H] | 0 | Intolerant | 0.598 | Possibly damaging | −5.957 | Deleterious |
| rs1381049817 | Tyr [Y]/Cys [C] | 0 | Intolerant | 0.439 | Benign | −8.015 | Deleterious |
| rs1336322605 | Phe [F]/Leu [L] | 0.67 | Tolerant | 0.002 | Benign | 1.022 | Neutral |
| rs140138702 | Leu [L]/Val [V] | 0.26 | Tolerant | 0.085 | Benign | −0.015 | Neutral |
| rs770197371 | Leu [L]/Arg [R] | 0 | Intolerant | 0.944 | Probably damaging | −4.636 | Deleterious |
| rs748401954 | Phe [F]/Ser [S] | 0 | Intolerant | 0.999 | Probably damaging | −7.315 | Deleterious |
| rs374342938 | Gly [G]/Ala [A] | 0.15 | Tolerant | 0.02 | Benign | 0.329 | Neutral |
| rs769037887 | Val [V]/Met [M] | 0.01 | Intolerant | 0.216 | Benign | 0.077 | Neutral |
| rs556023421 | Phe [F]/Leu [L] | 0 | Intolerant | 0.919 | Probably damaging | −5.436 | Deleterious |
| rs5397 | Leu [L]/Val [V] | 0.41 | Tolerant | 0.04 | Benign | −0.284 | Neutral |
| rs5398 | Phe [F]/Leu [L] | 0 | Intolerant | 0.424 | Benign | −5.276 | Deleterious |
| rs757137603 | Thr [T]/Ile [I] | 0.09 | Tolerant | 0.12 | Benign | −4.225 | Deleterious |
| rs1441249949 | Phe [F]/ Ile [I] | 0 | Intolerant | 0.616 | Possibly damaging | −4.39 | Deleterious |
| rs1195253424 | Val [V]/Ile [I] | 0 | Intolerant | 0.971 | Probably damaging | −0.908 | Neutral |
| rs753575081 | Pro [P]/Thr [T] | 0 | Intolerant | 0.994 | Probably damaging | −7.274 | Deleterious |
| rs777806589 | Lys [K]/Arg [R] | 0.38 | Tolerant | 0.601 | Possibly damaging | −1.518 | Neutral |
| rs766600474 | Ser [S]/Thr [T] | 1 | Tolerant | 0.104 | Benign | 1.006 | Neutral |
| rs766600474 | Ser [S]/Ala [A] | 0 | Intolerant | 0.304 | Benign | −1.65 | Neutral |
| rs1379944645 | Glu [E]/Lys [K] | 0.04 | Intolerant | 0.279 | Benign | −3.223 | Deleterious |
| rs1353603250 | Glu [E]/Gln [Q] | 0.19 | Tolerant | 0.759 | Possibly damaging | −2.031 | Neutral |
| rs1446857276 | Glu [E]/Asp [D] | 0.31 | Tolerant | 0.405 | Benign | −0.5 | Neutral |
| rs1283734332 | Ile [I]/Thr [T] | 0 | Intolerant | 0.999 | Probably damaging | −4.518 | Deleterious |
| rs1445660295 | Ala [A]/Val [V] | 0.02 | Intolerant | 0.444 | Benign | −3.184 | Deleterious |
| rs201797691 | Ala [A]/Thr [T] | 0.06 | Tolerant | 0.566 | Possibly damaging | −1.562 | Neutral |
| rs201797691 | Ala [A]/Pro [P] | 0.03 | Intolerant | 0.979 | Probably damaging | −2.518 | Deleterious |
| rs200160167 | Ala [A]/Glu [E] | 0.05 | Tolerant | 0.302 | Benign | −1.482 | Neutral |
| rs200160167 | Ala [A]/Val [V] | 0.03 | Intolerant | 0.566 | Possibly damaging | −2.596 | Deleterious |
| rs762305192 | Phe [F]/Leu [L] | 0 | Intolerant | 0.866 | Possibly damaging | −5.144 | Deleterious |
| rs776826621 | Lys [K]/Asn [N] | 0.2 | Tolerant | 0.005 | Benign | −1.549 | Neutral |
| rs5399 | Lys [K]/Asn [N] | 0.41 | Tolerant | 0.004 | Benign | −2.272 | Neutral |
| rs1412427073 | Gly [G]/Ser [S] | 0.28 | Tolerant | 0.004 | Benign | −1.628 | Neutral |
| rs966895511 | Ala [A]/Ser [S] | 0.83 | Tolerant | 0.004 | Benign | −0.449 | Neutral |
| rs1199349184 | Ala [A]/Val [V] | 0.24 | Tolerant | 0.004 | Benign | −1.611 | Neutral |
| rs374630641 | Arg [R]/Ser [S] | 0.94 | Tolerant | 0.001 | Benign | 0.45 | Neutral |
| rs771586150 | Pro [P]/Gln [Q] | 0.47 | Tolerant | 0.007 | Benign | −1.564 | Neutral |
| rs776597156 | Lys [K]/Asn[N] | 0.04 | Intolerant | 0.017 | Benign | −1.772 | Neutral |
| rs770462591 | Ala [A]/Asp [D] | 0.41 | Tolerant | 0.002 | Benign | −1.217 | Neutral |
| rs770462591 | Ala [A]/Val [V] | 0.16 | Tolerant | 0.007 | Benign | −1.309 | Neutral |
| rs141574520 | Phe [F]/Tyr [Y] | 1 | Tolerant | 0.003 | Benign | 0.369 | Neutral |
| rs147959014 | Gly [G]/Glu [E] | 0.01 | Intolerant | 0.104 | Benign | −2.153 | Neutral |
| rs752687355 | Glu [E]/Gly[G] | 0.03 | Intolerant | 0.009 | Benign | −2.391 | Neutral |
| rs781215842 | Thr [T]/Ser [S] | 0.82 | Tolerant | 0.004 | Benign | 0.326 | Neutral |
| rs758607933 | Val[V]/Met[M] | 0 | Intolerant | 0.004 | Benign | −1.155 | Neutral |
Variants with tolerance index ≤ 0.05 score of SIFT was considered as deleterious while others are taken to be tolerant. By PolyPhen, the variations with probabilistic score above 0.85 and 0.15 were considered to be “Probably damaging” and “possibly damaging” respectively while all the resting were categorized to be “Benign”. Provean score was equal to or below −2.5 it may be considered as deleterious and if the score was above −2.5, it was considered as neutral.
3.5 Analysis of nsSNPS using PolyPhen
To forecast the effects of function and structure 293 nsSNPs lying in the coding region of GLUT2 protein, PolyPhen-2 server was used. It permits three types of prediction score which is based on a “Sensitivity” as well as “Specificity”. Three prediction types are given by PolyPhen benign, possibly damaging or probably damaging. Out of 293 nsSNPs, 165 were considered to be benign. 65 were predicted to be possibly damaging and 77 were considered to be probably damaging (Table 2).
3.6 Analysis of SNPs using PROVEAN
PROVEAN gave score to predict neutral and deleterious effect of 293 nsSNPs present in coding region of GLUT2 protein. Score equal to or below −2.5 was considered as deleterious and above −2.5, as neutral. Out of 293 nsSNPs, 162 were predicted to be neutral and 138 were considered to be deleterious. It also gave the results of inframe deletion and insertion. Out of 4 inframe deletion 2 (rs772999215 and rs774721090) were shown to be deleterious 3 SNPs were inframe insertion (rs1161394690), (rs1463507753), (rs749789723) and no results were found for them (Table 2).
3.7 Analysis of nsSNPS using SNPeffect
The SNPeffect server was used to predict the effect of molecular phenotype of nsSNPs found in coding region of GLUT2 protein. Effect of 293 nsSNPs on aggregation tendency, amyloid propensity and chaperon binding tendency was specified by dTANGO, dWALTZ and dLIMBO score. Two significant effects, intrinsic aggregation propensity and protein stability were shown. In a protein sequence, aggregation propensity was identified by dTANGO. Out of 293 nsSNPs, 61 were detected to decrease the aggregation propensity, 27 to increase the aggregation propensity while 211 had no effect on aggregation propensity. dWALTZ indicated the score of amyloid propensity. 23 nsSNPs were shown to increase the amyloid propensity, 16 decreased the amyloid propensity and 257 had no effect on the amyloid propensity. According to dLIMBO, the chaperon binding tendency was given. None of them had any effect on chaperon binding tendency (Table 3).
| dbSNP rs#cluster id | Proteinresidue | dTANGO | Aggregationtendency | dWALTZ | Amyloidpropensity | dLIMBO | Chaperone bindingtendency |
|---|---|---|---|---|---|---|---|
| rs759495940 | Met [M]/Ile [I] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs773205789 | Thr [T]/Pro [P] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs200073044 | Asp [D]/His [H] | −101 | Decrease | 0.76 | No effect | 0 | No effect |
| rs1372689853 | Lys [K]/Glu [E] | −110.2 | Decreases | −0.49 | No effect | 0 | No effect |
| rs767313610 | Val [V]/Ile [I] | −5.8 | No effect | 0 | No effect | 0 | No effect |
| rs369700669 | Thr [T]/Asn [N] | −109.6 | Decreases | 0.01 | No effect | 0 | No effect |
| rs1481905618 | Phe [F]/Leu [L] | −1.1 | No effect | 0.12 | No effect | 0 | No effect |
| rs1247912820 | Thr [T]/Asn [N] | −9.9 | No effect | 0.97 | No effect | 0 | No effect |
| rs1247912820 | Thr [T]/Ser [S] | −2.7 | No effect | 0.34 | No effect | 0 | No effect |
| rs372441014 | Val [V]/Leu [L] | −0.5 | No effect | 0.12 | No effect | 0 | No effect |
| rs766364438 | Ile [I]/Thr [T] | −19.8 | No effect | 0.96 | No effect | 0 | No effect |
| rs867315854 | Ala [A]/Thr [T] | −5.6 | No effect | 0.04 | No effect | 0 | No effect |
| rs761992056 | Gly [G]/Asp [D] | −66 | Decreases | 2.67 | No effect | 0 | No effect |
| rs369781481 | Phe [F]/Leu [L] | –22.4 | No effect | 0.12 | No effect | 0 | No effect |
| rs1409436045 | Phe [F]/Tyr [Y] | −8.7 | No effect | 0.21 | No effect | 0 | No effect |
| rs1049223265 | Ile [I]/Thr [T] | 0 | No effect | −0.09 | No effect | 0 | No effect |
| rs1437312005 | Gly [G]/Ser [S] | 0 | No effect | 0.76 | No effect | 0 | No effect |
| rs1437312005 | Gly [G]/Arg [R] | 0 | No effect | −0.09 | No effect | 0 | No effect |
| rs775531825 | Asn [N]/Ser [S] | 0.1 | No effect | −0.08 | No effect | 0 | No effect |
| rs143528640 | Ala [A]/Thr [T] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs746158263 | Pro [P]/Thr [T] | 4 | No effect | −0.02 | No effect | 0 | No effect |
| rs1158195535 | Gln [Q]/Lys [K] | −4.3 | No effect | −559.66 | Decreases | 0 | No effect |
| rs1158195535 | Gln [Q]/Glu [E] | 11 | No effect | −62.94 | Decreases | 0 | No effect |
| rs1451394300 | Val [V]/Ile [I] | −0.9 | No effect | −116.97 | Decreases | 0 | No effect |
| rs1477523180 | Ile [I]/Leu [L] | −2.5 | No effect | −3.89 | No effect | 0 | No effect |
| rs1360464436 | Ile [I]/Lys [K] | −4.3 | No effect | −417.77 | Decreases | 0 | No effect |
| rs1176350402 | Ile [I]/Thr [T] | −4.3 | No effect | −571.42 | Decreases | 0 | No effect |
| rs758670698 | Arg [R]/Ile [I] | 110.7 | Increases | −0.73 | No effect | 0 | No effect |
| rs760618624 | His [H]/Tyr [Y] | 1.1 | No effect | 0 | No effect | 0 | No effect |
| rs775791143 | Val [V]/Ile [I] | 0 | No effect | 0.01 | No effect | 0 | No effect |
| rs149108283 | Val [V]/Asp [D] | 1.7 | No effect | −0.72 | No effect | 0 | No effect |
| rs149108283 | Val [V]/Ala [A] | 0 | No effect | 0.01 | No effect | 0 | No effect |
| rs1159338702 | Gly [G]/Ser [S] | 0 | No effect | 0.02 | No effect | 0 | No effect |
| rs561765982 | Val [V]/Ile [I] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs983907950 | Pro [P]/Ser [S] | 24.1 | No effect | −0.27 | No effect | 0 | No effect |
| rs1211075508 | Leu [L]/Pro [P] | 0 | No effect | 0.23 | No effect | 0 | No effect |
| rs1311902495 | Asp [D]/Asn [N] | −1.9 | No effect | 1.14 | No effect | 0 | No effect |
| rs1311902495 | Asp [D]/Tyr [Y] | −1.9 | No effect | 1.01 | No effect | 0 | No effect |
| rs771477447 | Arg [R]/Gly [G] | 0.7 | No effect | 0.07 | No effect | 0 | No effect |
| rs145210664 | Arg [R]/Gln [Q] | 0.6 | No effect | −0.52 | No effect | 0 | No effect |
| rs546539032 | Lys [K]/Asn [N] | 2.3 | No effect | 0.11 | No effect | 0 | No effect |
| rs747555903 | Val [V]/Ile [I] | −0.1 | No effect | −58.27 | Decreases | 0 | No effect |
| rs977284195 | Ile [I]/Thr [T] | −1 | No effect | 0.02 | No effect | 0 | No effect |
| rs780903829 | Ile [I]/Met [M] | −1 | No effect | 0.01 | No effect | 0 | No effect |
| rs1373290524 | Ser [S]/Thr [T] | 1 | No effect | 0 | No effect | 0 | No effect |
| rs1310901426 | Thr [T]/Ala [A] | −0.1 | No effect | 0.02 | No effect | 0 | No effect |
| rs1354126805 | Thr [T]/Arg [R] | 1.6 | No effect | −0.03 | No effect | 0 | No effect |
| rs754585542 | Asp [D]/Asn [N] | −1.9 | No effect | 0.76 | No effect | 0 | No effect |
| rs1217666649 | Asp [D]/Glu [E] | 0 | No effect | 0.01 | No effect | 0 | No effect |
| rs1391257598 | Pro [P]/Thr [T] | 0 | No effect | 0.33 | No effect | 0 | No effect |
| rs7637863 | Pro [P]/Leu [L] | 6.5 | No effect | 7.11 | No effect | 0 | No effect |
| rs779977931 | Thr [T]/Lys [K] | 0 | No effect | −0.35 | No effect | 0 | No effect |
| rs1182852354 | Ile [I]/Val [V] | 0 | No effect | −0.44 | No effect | 0 | No effect |
| rs750405382 | Met [M]/Val [V] | 3.5 | No effect | 0.26 | No effect | 0 | No effect |
| rs1207297111 | Asn [N]/Asp [D] | 1.7 | No effect | −0.72 | No effect | 0 | No effect |
| rs1342979475 | Asn [N]/Thr [T] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs1274084408 | Pro [P]/Ala [A] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs778655073 | Pro [P]/Leu [L] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs549263048 | Trp [W]/Arg [R] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs531049536 | Trp [W]/Cys [C] | 0.1 | No effect | −0.05 | No effect | 0 | No effect |
| rs150851401 | Glu [E]/Lys [K] | −1.3 | No effect | 0.86 | No effect | 0 | No effect |
| rs766762468 | Thr [T]/Ser [S] | −3.4 | No effect | 0.72 | No effect | 0 | No effect |
| rs766762468 | T (Thr) > I (Ile) | 56.4 | Increases | −14.66 | No effect | 0 | No effect |
| rs763255363 | Ala [A]/Ser [S] | −17.7 | No effect | 6.87 | No effect | 0 | No effect |
| rs144715667 | Ile [I]/Val [V] | 12 | No effect | −212.15 | Decreases | 0 | No effect |
| rs1415169647 | Met [M]/Arg [R] | −820.3 | Decreases | 227.06 | Increases | 0 | No effect |
| rs1407375423 | Trp [W]/Cys [C] | −662.7 | Decreases | 200.31 | Increases | 0 | No effect |
| rs1800572 | Val [V]/Ile [I] | −16 | No effect | 5.29 | No effect | 0 | No effect |
| rs1800572 | V (Val) > L (Leu) | −161.8 | Decreases | 45.81 | No effect | 0 | No effect |
| rs770135219 | Val [V]/Ala [A] | −382.9 | Decreases | 93.15 | Increases | 0 | No effect |
| rs1399091893 | Ala [A]/Val [V] | 456.9 | Increases | −154.77 | Decreases | 0 | No effect |
| rs1332764085 | Val [V]/Ile [I] | −12.4 | No effect | 3.22 | No effect | 0 | No effect |
| rs5400 | Thr [T]/Ile [I] | 142.4 | Increases | −3.5 | No effect | 0 | No effect |
| rs377238940 | Ala [A]/Pro [P] | −7.5 | No effect | −7.19 | No effect | 0 | No effect |
| rs768407637 | Gly [G]/Val [V] | 395.8 | Increases | −4.57 | No effect | 0 | No effect |
| rs753980727 | Trp [W]/Cys [C] | −4.8 | No effect | 0 | No effect | 0 | No effect |
| rs746632604 | Gly [G]/Ala [A] | 3.2 | No effect | −0.03 | No effect | 0 | No effect |
| rs772002572 | Thr [T]/Ile [I] | 3.6 | No effect | −0.02 | No effect | 0 | No effect |
| rs1476520648 | Ile [I]/Asn [N] | 6.4 | No effect | 0.04 | No effect | 0 | No effect |
| rs760201098 | Ala [A]/Asp [D] | 179.3 | Increases | −3.71 | No effect | 0 | No effect |
| rs1267904495 | Met [M]/Thr [T] | −39.4 | No effect | 0.97 | No effect | 0 | No effect |
| rs1212980167 | Met [M]/Ile [I] | 212.1 | Increases | −4.25 | No effect | 0 | No effect |
| rs367856967 | Val [V]/Ala [A] | −393 | Decreases | 11.97 | No effect | 0 | No effect |
| rs970550665 | Ala [A]/Gly [G] | −345 | Decreases | −1.75 | No effect | 0 | No effect |
| rs775283150 | Ile [I]/Phe [F] | 13.1 | No effect | −3.23 | No effect | 0 | No effect |
| rs913419413 | Leu [L]/Arg [R] | −1039.9 | Decreases | −4.86 | No effect | 0 | No effect |
| rs771843187 | Ser [S]/Pro [P] | −962.7 | Decreases | 49.25 | No effect | 0 | No effect |
| rs144125084 | Val [V]/Leu [L] | −119 | Decreases | 5.37 | No effect | 0 | No effect |
| rs993833041 | Val [V]/Ala [A] | −567.9 | Decreases | 28.42 | No effect | 0 | No effect |
| rs1300072764 | Gly [G]/Glu [E] | −327.2 | Decreases | 5.99 | No effect | 0 | No effect |
| rs778548964 | Leu [L]/Phe [F] | 87.5 | Increases | −2.88 | No effect | 0 | No effect |
| rs1016384738 | Met [M]/Lys [K] | −378.4 | Decreases | 11.06 | No effect | 0 | No effect |
| rs770941010 | Gly [G]/Arg [R] | −228.7 | Decreases | 6.26 | No effect | 0 | No effect |
| rs777718289 | Gly [G]/Glu [E] | 3.5 | No effect | −0.81 | No effect | 0 | No effect |
| rs777718289 | Gly [G]/Val [V] | 0.6 | No effect | 0.19 | No effect | 0 | No effect |
| rs372621339 | Pro [P]/Arg [R] | −2.6 | No effect | 1.25 | No effect | 0 | No effect |
| rs747025551 | Ile [I]/Thr [T] | −254.4 | Decreases | −380.89 | Decreases | 0 | No effect |
| rs376064965 | Leu [L]/Phe [F] | 90.6 | Increases | 99.92 | Increases | 0 | No effect |
| rs1188886679 | Ile [I]/Leu [L] | −87.4 | Decreases | −29.47 | No effect | 0 | No effect |
| rs1188886679 | Ile [I]/Val [V] | 9.3 | No effect | −467.67 | Decreases | 0 | No effect |
| rs192720796 | Ile [I]/Lys [K] | −292.7 | Decreases | −470.84 | Decreases | 0 | No effect |
| rs910976682 | Ala [A]/Val [V] | 190.3 | Increases | −165.8 | Decreases | 0 | No effect |
| rs750836049 | Gly [G]/Arg [R] | −136.3 | Decreases | 37.18 | No effect | 0 | No effect |
| rs1278964539 | Arg [R]/Lys [K] | −0.1 | No effect | −0.07 | No effect | 0 | No effect |
| rs1231468128 | Leu [L]/Gln [Q] | −8 | No effect | −0.23 | No effect | 0 | No effect |
| rs1445887606 | Tyr [Y]/His [H] | −9.1 | No effect | −6.28 | No effect | 0 | No effect |
| rs1271546287 | Ile [I]/Thr [T] | −10.1 | No effect | −12.03 | No effect | 0 | No effect |
| rs760095835 | Gly [G]/Asp [D] | −2.3 | No effect | −0.62 | No effect | 0 | No effect |
| rs1335888503 | Val [V]/Leu [L] | 0 | No effect | −0.02 | No effect | 0 | No effect |
| rs1293130515 | Met [M]/Thr [T] | 0 | No effect | −0.02 | No effect | 0 | No effect |
| rs1019696977 | Ile [I]/Val [V] | 0 | No effect | −5.05 | No effect | 0 | No effect |
| rs144822218 | Gly [G]/Ser [S] | 0 | No effect | 43.87 | No effect | 0 | No effect |
| rs759047405 | Gly [G]/Asp [D] | 1.7 | No effect | −6.74 | No effect | 0 | No effect |
| rs1441606652 | Ala [A]/Val [V] | 0 | No effect | 7.16 | No effect | 0 | No effect |
| rs368626129 | Ala [A]/Thr [T] | 0 | No effect | 0.02 | No effect | 0 | No effect |
| rs368626129 | Ala [A]/Ser [S] | 0 | No effect | 0.01 | No effect | 0 | No effect |
| rs200213178 | Ala [A]/Thr [T] | −0.1 | No effect | 0.01 | No effect | 0 | No effect |
| rs200213178 | Ala [A]/Pro [P] | −0.1 | No effect | 0 | No effect | 0 | No effect |
| rs748052042 | Leu [L]/Phe [F] | 0.7 | No effect | 0 | No effect | 0 | No effect |
| rs1412289847 | Gly [G]/Ser [S] | 0.1 | No effect | 0.02 | No effect | 0 | No effect |
| rs776498787 | Gly [G]/Asp [D] | 0.4 | No effect | −0.61 | No effect | 0 | No effect |
| rs779065938 | Leu [L]/Val [V] | 36.5 | No effect | 146.08 | Increases | 0 | No effect |
| rs1469335096 | Ala [A]/Thr [T] | −20.5 | No effect | 4.53 | No effect | 0 | No effect |
| rs771182536 | Ile [I]/Asn [N] | −603.7 | Decreases | 96.63 | Increases | 0 | No effect |
| rs771182536 | Ile [I]/Thr [T] | −306.2 | Decreases | 63.05 | Increases | 0 | No effect |
| rs121909741 | Val [V]/Ile [I] | −2.4 | No effect | −10.45 | No effect | 0 | No effect |
| rs149460434 | Thr [T]/Lys [K] | 502 | Increases | 54.29 | Increases | 0 | No effect |
| rs149460434 | Thr [T]/Met [M] | 14.7 | No effect | −16.93 | No effect | 0 | No effect |
| rs1276756236 | Leu [L]/Ile [I] | 16.9 | No effect | −17.56 | No effect | 0 | No effect |
| rs779591826 | Ile [I]/Met [M] | −147 | Decreases | 82.45 | Increases | 0 | No effect |
| rs1262860274 | Ile [I]/Thr [T] | −148.5 | Decreases | 77.8 | Increases | 0 | No effect |
| rs1186359171 | Gly [G]/Ser [S] | 12.2 | No effect | −13.3 | No effect | 0 | No effect |
| rs1215469128 | Leu [L]/Ser [S] | 0.7 | No effect | −9.46 | No effect | 0 | No effect |
| rs1347267249 | Asn [N]/His [H] | 1 | No effect | −3.73 | No effect | 0 | No effect |
| rs573292685 | Asn [N]/Ser [S] | 0.9 | No effect | −5.01 | No effect | 0 | No effect |
| rs764799427 | Asp [D]/Val [V] | 905.2 | Increases | −37.64 | No effect | 0 | No effect |
| rs1380319602 | Ile [I]/Asn [N] | −54 | Decreases | −78.29 | Decreases | 0 | No effect |
| rs760641937 | Gly [G]/Ala [A] | 209.4 | Increases | −34.8 | No effect | 0 | No effect |
| rs1413841367 | Leu [L]/Pro [P] | −45.1 | No effect | 8.09 | No effect | 0 | No effect |
| rs771075989 | Val [V]/Met [M] | −2.4 | No effect | 0.47 | No effect | 0 | No effect |
| rs773581866 | Arg [R]/Gly [G] | 174.1 | Increases | −49 | No effect | 0 | No effect |
| rs770126214 | Leu [L]/Ile [I] | 60.4 | Increases | −3.97 | No effect | 0 | No effect |
| rs1374154306 | Leu [L]/Gln [Q] | −491.6 | Decreases | 317.25 | Increases | 0 | No effect |
| rs748588515 | Leu [L]/Phe [F] | 15.7 | No effect | 32.66 | No effect | 0 | No effect |
| rs757087261 | Phe [F]/Ile [I] | −4.5 | No effect | −9.69 | No effect | 0 | No effect |
| rs777020657 | Phe [F]/Cys [C] | −264.3 | Decreases | 1.76 | No effect | 0 | No effect |
| rs777020657 | F (Phe) > S (Ser) | −295.4 | Decreases | 40.37 | No effect | 0 | No effect |
| rs769089021 | Ser [S]/Asn [N] | −0.1 | No effect | 0 | No effect | 0 | No effect |
| rs780381836 | Arg [R]/Gly [G] | 4.2 | No effect | 147.36 | Increases | 0 | No effect |
| rs1480881050 | Tyr [Y]/His [H] | −1.6 | No effect | −8.07 | No effect | 0 | No effect |
| rs1250722271 | Tyr [Y]/His [H] | −2.3 | No effect | −8.13 | No effect | 0 | No effect |
| rs1158317020 | Tyr [Y]/Phe [F] | 7.6 | No effect | −6.38 | No effect | 0 | No effect |
| rs867996396 | Ile [I]/Asn [N] | −2.3 | No effect | −8.12 | No effect | 0 | No effect |
| rs867996396 | I (Ile) > T (Thr) | −2.3 | No effect | −8.19 | No effect | 0 | No effect |
| rs536261161 | Lys [K]/Asn [N] | 62.3 | Increases | 385.31 | Increases | 0 | No effect |
| rs745373269 | Asp [D]/Asn [N] | −4.2 | No effect | 0.87 | No effect | 0 | No effect |
| rs745373269 | Asp [D]/His [H] | −4.2 | No effect | 1.41 | No effect | 0 | No effect |
| rs1367431424 | Glu [E]/Ala [A] | 11.5 | No effect | 0.95 | No effect | 0 | No effect |
| rs865881030 | Glu [E]/Lys [K] | −1.8 | No effect | 1.2 | No effect | 0 | No effect |
| rs778607566 | Glu [E]/Gly [G] | 4 | No effect | 1.31 | No effect | 0 | No effect |
| rs1309254226 | Glu [E]/Asp [D] | −0.1 | No effect | 0.45 | No effect | 0 | No effect |
| rs777225980 | Ser [S]/Arg [R] | −0.2 | No effect | −0.6 | No effect | 0 | No effect |
| rs76026576 | Leu [L]/Phe [F] | 0 | No effect | 0.07 | No effect | 0 | No effect |
| rs1490504926 | Asp [D]/Asn [N] | −1.9 | No effect | 0.74 | No effect | 0 | No effect |
| rs935009475 | Asp [D]/Glu [E] | 0 | No effect | 0.01 | No effect | 0 | No effect |
| rs140285191 | Asp [D]/Asn [N] | −1.9 | No effect | 1.25 | No effect | 0 | No effect |
| rs140285191 | Asp [D]/Tyr [Y] | −1.9 | No effect | 2.54 | No effect | 0 | No effect |
| rs754932741 | Met [M]/Ile [I] | 0 | No effect | 0.08 | No effect | 0 | No effect |
| rs750579210 | Arg [R]/Gly [G] | −0.2 | No effect | 0.03 | No effect | 0 | No effect |
| rs1304842107 | Lys [K]/Gln [Q] | −0.2 | No effect | 0.03 | No effect | 0 | No effect |
| rs765426962 | Lys [K]/Thr [T] | −0.2 | No effect | 0.03 | No effect | 0 | No effect |
| rs761756532 | Lys [K]/Asn [N] | −0.2 | No effect | 0.03 | No effect | 0 | No effect |
| rs1329237779 | Glu [E]/Lys [K] | −1.9 | No effect | 0.76 | No effect | 0 | No effect |
| rs1384542256 | Glu [E]/Ala [A] | −1.9 | No effect | 0.76 | No effect | 0 | No effect |
| rs776912318 | Ser [S]/Arg [R] | −1.3 | No effect | −0.29 | No effect | 0 | No effect |
| rs776912318 | Ser [S]/Cys [C] | 0.1 | No effect | −0.04 | No effect | 0 | No effect |
| rs764161243 | Lys [K]/Thr [T] | 123 | Increases | −19.4 | No effect | 0 | No effect |
| rs780873643 | Val [V]/Gly [G] | −69.1 | Decreases | 4.31 | No effect | 0 | No effect |
| rs775691314 | Ser [S]/Cys [C] | 30.7 | No effect | −9.87 | No effect | 0 | No effect |
| rs772619265 | Ile [I]/Val [V] | 10.1 | No effect | 97.69 | Increases | 0 | No effect |
| rs760061096 | Ile [I]/Lys [K] | −201.9 | Decreases | −43.38 | No effect | 0 | No effect |
| rs1205719797 | Leu [L]/His [H] | −203 | Decreases | −200.41 | Decreases | 0 | No effect |
| rs1364855365 | Thr [T]/Ser [S] | −54.4 | Decreases | 69.79 | Increases | 0 | No effect |
| rs368432491 | Asn [N]/Ser [S] | 5.5 | No effect | −2.26 | No effect | 0 | No effect |
| rs182778895 | Ser [S]/Pro [P] | −4.4 | No effect | −0.59 | No effect | 0 | No effect |
| rs777540740 | Ser [S]/Cys [C] | 0.9 | No effect | 0.46 | No effect | 0 | No effect |
| rs769325995 | Tyr [Y]/His [H] | −0.9 | No effect | −0.61 | No effect | 0 | No effect |
| rs374492763 | Arg [R]/Gln [Q] | 0.6 | No effect | 0.05 | No effect | 0 | No effect |
| rs374492763 | Arg [R]/Leu [L] | 0.5 | No effect | 0.06 | No effect | 0 | No effect |
| rs938526894 | Leu [L]/Pro [P] | −548.4 | Decreases | 0.15 | No effect | 0 | No effect |
| rs1312418962 | Met [M]/Thr [T] | −36.1 | No effect | 0.01 | No effect | 0 | No effect |
| rs1421580115 | Val [V]/Met [M] | −30.3 | No effect | 0.05 | No effect | 0 | No effect |
| rs1324205444 | Ala [A]/Thr [T] | −4.9 | No effect | −0.03 | No effect | 0 | No effect |
| rs1324205444 | Ala [A]/Ser [S] | −15 | No effect | −0.04 | No effect | 0 | No effect |
| rs780067980 | Gly [G]/Arg [R] | −12.6 | No effect | 0.05 | No effect | 0 | No effect |
| rs369101584 | Asn [N]/Ser [S] | 42.5 | No effect | −0.2 | No effect | 0 | No effect |
| rs757366672 | Gly [G]/Cys [C] | 33.1 | No effect | −190.41 | Decreases | 0 | No effect |
| rs767670296 | Ile [I]/Asn [N] | −470.3 | Decreases | −49.94 | No effect | 0 | No effect |
| rs1272816101 | Ile [I]/Met [M] | −365.7 | Decreases | −30.37 | No effect | 0 | No effect |
| rs759952425 | Tyr [Y]/His [H] | −553.7 | Decreases | −590.8 | Decreases | 0 | No effect |
| rs751917665 | Thr [T]/Met [M] | 14.8 | No effect | −0.05 | No effect | 0 | No effect |
| rs1441375275 | Ala [A]/Thr [T] | −2.3 | No effect | 0.02 | No effect | 0 | No effect |
| rs763345848 | Gly [G]/Asp [D] | −8.9 | No effect | −0.68 | No effect | 0 | No effect |
| rs1461795294 | Ser [S]/Gly [G] | −0.1 | No effect | 0 | No effect | 0 | No effect |
| rs773717998 | Thr [T]/Asn [N] | −0.9 | No effect | 0.03 | No effect | 0 | No effect |
| rs1162318193 | Ile [I]/Thr [T] | −61.4 | Decreases | 0 | No effect | 0 | No effect |
| rs1050103029 | Val [V]/Ala [A] | −116.3 | Decreases | 0.03 | No effect | 0 | No effect |
| rs764683908 | Gly [G]/Asp [D] | −148.2 | Decreases | 2.22 | No effect | 0 | No effect |
| rs776435170 | Ala [A]/Thr [T] | −37.9 | No effect | 0.01 | No effect | 0 | No effect |
| rs1236921754 | Ala [A]/Val [V] | 274.6 | Increases | 0 | No effect | 0 | No effect |
| rs746863503 | Met [M]/Arg [R] | −234.8 | Decreases | 3.51 | No effect | 0 | No effect |
| rs775407568 | Met [M]/Ile [I] | 86.5 | Increases | 0.83 | No effect | 0 | No effect |
| rs771855037 | Ala [A]/Thr [T] | −1.1 | No effect | 0.01 | No effect | 0 | No effect |
| rs140815551 | Val [V]/Ile [I] | −0.1 | No effect | 0.01 | No effect | 0 | No effect |
| rs1348497054 | Ser [S]/Cys [C] | 0.2 | No effect | −0.05 | No effect | 0 | No effect |
| rs1469035471 | Val [V]/Leu [L] | −0.2 | No effect | 0.16 | No effect | 0 | No effect |
| rs372845210 | Leu [L]/Ile [I] | 0.5 | No effect | 0.06 | No effect | 0 | No effect |
| rs372845210 | Leu [L]/Phe [F] | 0.5 | No effect | 0.03 | No effect | 0 | No effect |
| rs1380054283 | Glu [E]/Gln [Q] | −16.6 | No effect | 0.77 | No effect | 0 | No effect |
| rs999185720 | Glu [E]/Asp [D] | −0.1 | No effect | 0 | No effect | 0 | No effect |
| rs745619267 | Lys [K]/Asn [N] | −10.2 | No effect | 0.03 | No effect | 0 | No effect |
| rs76362149 | Ala [A]/Ser [S] | −0.1 | No effect | 0 | No effect | 0 | No effect |
| rs781225543 | Arg [R]/Gln [Q] | 1.3 | No effect | −0.54 | No effect | 0 | No effect |
| rs1321655963 | Arg [R]/Cys [C] | 10 | No effect | −10.88 | No effect | 0 | No effect |
| rs755000812 | Arg [R]/His [H] | 8.8 | No effect | −10.45 | No effect | 0 | No effect |
| rs1223071449 | Phe [F]/Leu [L] | −5 | No effect | −25.18 | No effect | 0 | No effect |
| rs1430684701 | Leu [L]/Pro [P] | −10.5 | No effect | −27.2 | No effect | 0 | No effect |
| rs747262541 | Ser [S]/Asn [N] | −3.6 | No effect | 46.65 | No effect | 0 | No effect |
| rs868182136 | Gly [G]/Glu [E] | 286.1 | Increases | 249.54 | Increases | 0 | No effect |
| rs780255530 | Met [M]/Val [V] | 63.2 | Increases | −24.52 | No effect | 0 | No effect |
| rs758699271 | Met [M]/Ile [I] | 62.1 | Increases | −24.31 | No effect | 0 | No effect |
| rs946622803 | Phe [F]/Leu [L] | −20.9 | No effect | 28.63 | No effect | 0 | No effect |
| rs1381085405 | Phe [F]/Tyr [Y] | −39.4 | No effect | 54.3 | Increases | 0 | No effect |
| rs1381085405 | Phe [F]/Ser [S] | −178.9 | Decreases | 280.03 | Increases | 0 | No effect |
| rs750782646 | Ile [I]/Asn [N] | −318.3 | Decreases | 268.28 | Increases | 0 | No effect |
| rs765728439 | Met [M]/Thr [T] | −3.8 | No effect | 14.75 | No effect | 0 | No effect |
| rs757805176 | Gly [G]/Arg [R] | −191 | Decreases | 26.9 | No effect | 0 | No effect |
| rs757805176 | Gly [G]/Arg [R] | −191 | Decreases | 26.9 | No effect | 0 | No effect |
| rs1199637811 | Val [V]/Gly [G] | −117.4 | Decreases | 11.9 | No effect | 0 | No effect |
| rs121909747 | Leu [L]/Arg [R] | −125.4 | Decreases | 11.4 | No effect | 0 | No effect |
| rs 121,909,747 | L (Leu) > P (Pro) | −133.3 | Decreases | 12.33 | No effect | 0 | No effect |
| rs760200790 | Leu [L]/Arg [R] | −62.3 | Decreases | 8.37 | No effect | 0 | No effect |
| rs766191732 | Phe [F]/Leu [L] | −25.2 | No effect | 0.37 | No effect | 0 | No effect |
| rs1464417991 | Ser [S]/Pro [P] | −94.9 | Decreases | 1.83 | No effect | 0 | No effect |
| rs762668792 | Val [V]/Glu [E] | −565.8 | Decreases | 46.57 | No effect | 0 | No effect |
| rs1457657980 | Met [M]/Val [V] | 23.2 | No effect | −2.74 | No effect | 0 | No effect |
| rs374702599 | Ile [I]/Thr [T] | −72.2 | Decreases | 43.39 | No effect | 0 | No effect |
| rs1419532672 | Ile [I]/Val [V] | −0.1 | No effect | −2.52 | No effect | 0 | No effect |
| rs2229608 | Ile [I]/Thr [T] | 5.3 | No effect | −1.6 | No effect | 0 | No effect |
| rs760729620 | Phe [F]/Ser [S] | −14.9 | No effect | −2.61 | No effect | 0 | No effect |
| rs140791627 | Ser [S]/Cys [C] | 85.1 | Increases | −1.9 | No effect | 0 | No effect |
| rs746136121 | Phe [F]/Leu [L] | −35.7 | No effect | 2.96 | No effect | 0 | No effect |
| rs1353890919 | Phe [F]/Cys [C] | 4.5 | No effect | 5.85 | No effect | 0 | No effect |
| rs966424064 | Ile [I]/Thr [T] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs779212294 | Ile [I]/Met [M] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs121909744 | Pro [P]/Arg [R] | 9.1 | No effect | −0.44 | No effect | 0 | No effect |
| rs121909744 | Pro [P]/Leu [L] | −0.1 | No effect | 4.65 | No effect | 0 | No effect |
| rs1309197020 | Ile [I]/Met [M] | −0.2 | No effect | −0.05 | No effect | 0 | No effect |
| rs1309197020 | I (Ile) > I (Ile) | 0 | No effect | 0 | No effect | 0 | No effect |
| rs749661374 | Met [M]/Val [V] | 230.5 | Increases | −18.16 | No effect | 0 | No effect |
| rs778490867 | Met [M]/Thr [T] | −27.3 | No effect | 2.19 | No effect | 0 | No effect |
| rs28928874 | Val [V]/Glu [E] | −56.9 | Decreases | –33.24 | No effect | 0 | No effect |
| rs367980651 | Arg [R]/Cys [C] | 17.1 | No effect | −2.91 | No effect | 0 | No effect |
| rs75144723 | Arg [R]/His [H] | 16.7 | No effect | −2.79 | No effect | 0 | No effect |
| rs754405476 | Ala [A]/Thr [T] | −15.2 | No effect | −42.65 | No effect | 0 | No effect |
| rs1379813904 | Ala [A]/Glu [E] | −158.8 | Decreases | −15.31 | No effect | 0 | No effect |
| rs751226875 | Ile [I]/Thr [T] | −147.2 | Decreases | −53.16 | Decreases | 0 | No effect |
| rs762675284 | Ala [A]/Ser [S] | −118.2 | Decreases | 48.11 | No effect | 0 | No effect |
| rs1262058831 | Ala [A]/Val [V] | 346.5 | Increases | 54.41 | Increases | 0 | No effect |
| rs758246412 | Ala [A]/Glu [E] | −113.4 | Decreases | 126.69 | Increases | 0 | No effect |
| rs1203908311 | Asn [N]/Ser [S] | 90 | Increases | −44.34 | No effect | 0 | No effect |
| rs765196886 | Ile [I]/Leu [L] | 18.3 | No effect | 38.73 | No effect | 0 | No effect |
| rs761784655 | Ile [I]/Thr [T] | −138.3 | Decreases | 205.72 | Increases | 0 | No effect |
| rs776395971 | Val [V]/Ala [A] | −96.7 | Decreases | 204.13 | Increases | 0 | No effect |
| rs1238600269 | Ala [A]/Thr [T] | 10.6 | No effect | 20.07 | No effect | 0 | No effect |
| rs1418589512 | Cys [C]/Arg [R] | −104.2 | Decreases | 339.43 | Increases | 0 | No effect |
| rs759480075 | Tyr [Y]/His [H] | −83.6 | Decreases | −6.52 | No effect | 0 | No effect |
| rs771274850 | Ile [I]/Thr [T] | −80 | Decreases | −6.87 | No effect | 0 | No effect |
| rs749710583 | Ala [A]/Glu [E] | −69.6 | Decreases | −5.77 | No effect | 0 | No effect |
| rs749710583 | Ala [A]/Val [V] | 142 | Increases | −15.87 | No effect | 0 | No effect |
| rs774542648 | Gly [G]/Arg [R] | 6 | No effect | 0 | No effect | 0 | No effect |
| rs1272353608 | Pro [P]/His [H] | −169.7 | Decreases | −11.73 | No effect | 0 | No effect |
| rs1381049817 | Tyr [Y]/Cys [C] | 12.4 | No effect | −0.04 | No effect | 0 | No effect |
| rs1336322605 | Phe [F]/Leu [L] | −0.3 | No effect | 0 | No effect | 0 | No effect |
| rs140138702 | Leu [L]/Val [V] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs770197371 | Leu [L]/Arg [R] | −614.7 | Decreases | 0.4 | No effect | 0 | No effect |
| rs748401954 | Phe [F]/Ser [S] | −6.2 | No effect | 0.01 | No effect | 0 | No effect |
| rs374342938 | Gly [G]/Ala [A] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs769037887 | Val [V]/Met [M] | −0.3 | No effect | 0.04 | No effect | 0 | No effect |
| rs556023421 | Phe [F]/Leu [L] | −0.4 | No effect | 0.01 | No effect | 0 | No effect |
| rs5397 | Leu [L]/Val [V] | 0.9 | No effect | 0 | No effect | 0 | No effect |
| rs5398 | Phe [F]/Leu [L] | −4.5 | No effect | 0.01 | No effect | 0 | No effect |
| rs757137603 | Thr [T]/Ile [I] | 19.1 | No effect | 0 | No effect | 0 | No effect |
| rs1441249949 | Phe [F]/ Ile [I] | −2.8 | No effect | 0.01 | No effect | 0 | No effect |
| rs1195253424 | Val [V]/Ile [I] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs753575081 | Pro [P]/Thr [T] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs777806589 | Lys [K]/Arg [R] | 0 | No effect | 0.07 | No effect | 0 | No effect |
| rs766600474 | Ser [S]/Thr [T] | 0 | No effect | 27.03 | No effect | 0 | No effect |
| rs766600474 | Ser [S]/Ala [A] | 0 | No effect | 151.16 | Increases | 0 | No effect |
| rs1379944645 | Glu [E]/Lys [K] | −1.9 | No effect | −13.73 | No effect | 0 | No effect |
| rs1353603250 | Glu [E]/Gln [Q] | −1.9 | No effect | −13.48 | No effect | 0 | No effect |
| rs1446857276 | Glu [E]/Asp [D] | 0 | No effect | −14.56 | No effect | 0 | No effect |
| rs1283734332 | Ile [I]/Thr [T] | 0 | No effect | −14.46 | No effect | 0 | No effect |
| rs1445660295 | Ala [A]/Val [V] | 0 | No effect | 16.65 | No effect | 0 | No effect |
| rs201797691 | Ala [A]/Thr [T] | 0 | No effect | 0.17 | No effect | 0 | No effect |
| rs201797691 | Ala [A]/Pro [P] | 0 | No effect | 0.21 | No effect | 0 | No effect |
| rs200160167 | Ala [A]/Glu [E] | 1.7 | No effect | −0.33 | No effect | 0 | No effect |
| rs200160167 | Ala [A]/Val [V] | 0 | No effect | 31.4 | No effect | 0 | No effect |
| rs762305192 | Phe [F]/Leu [L] | 0 | No effect | −2.56 | No effect | 0 | No effect |
| rs776826621 | Lys [K]/Asn [N] | −0.2 | No effect | 0.23 | No effect | 0 | No effect |
| rs5399 | Lys [K]/Asn [N] | −0.2 | No effect | 0.05 | No effect | 0 | No effect |
| rs1412427073 | Gly [G]/Ser [S] | 0 | No effect | 0.01 | No effect | 0 | No effect |
| rs966895511 | Ala [A]/Ser [S] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs1199349184 | Ala [A]/Val [V] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs374630641 | Arg [R]/Ser [S] | −0.2 | No effect | 0.03 | No effect | 0 | No effect |
| rs771586150 | Pro [P]/Gln [Q] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs776597156 | Lys[K]/Asn[N] | −0.2 | No effect | 0.03 | No effect | 0 | No effect |
| rs770462591 | Ala [A]/Asp [D] | 3 | No effect | −0.72 | No effect | 0 | No effect |
| rs770462591 | Ala [A]/Val [V] | 8.5 | No effect | 0 | No effect | 0 | No effect |
| rs141574520 | Phe [F]/Tyr [Y] | −2.7 | No effect | 0.06 | No effect | 0 | No effect |
| rs147959014 | Gly [G]/Glu [E] | 2.8 | No effect | −0.72 | No effect | 0 | No effect |
| rs752687355 | Glu[E]/Gly[G] | −4.4 | No effect | 0.76 | No effect | 0 | No effect |
| rs781215842 | Thr [T]/Ser [S] | 0 | No effect | 0 | No effect | 0 | No effect |
| rs758607933 | Val[V]/Met[M] | 0 | No effect | 0 | No effect | 0 | No effect |
Variations with dTANGO, dWALTZ and dLIMBO between −50 and 50 were supposed to have no effect on aggregation tendency, amyloid propensity and chaperone binding tendency, respectively.
4 Discussion
For most living cells, glucose is a vital energy source and an important substrate for biochemical reaction. There are two types of glucose transporters. GLUTs and SGLTs. SGLT family members consist of 580–718 amino acids and 60–80-kDa weight. GLUTs are proteins containing 12 membrane-spanning regions with intracellularl carboxyl and amino terminals. The sequence of GLUT proteins has been known to show 28–65% resemblance with GLUT1. The GLUTs symport glucose by facilitated diffusion mechanism across the plasma membrane (Navale and Paranjape, 2016). On the basis of phylogenetic relationship, 14 human GLUT proteins are grouped into three classes. Class I includes GLUT 1–4 and 14, in class II has GLUT 5,9,7, 11 and class III contains GLUT 6,13,8,12,10 (Manolescu et al., 2007). GLUT2 is a low affinity glucose transporter with affinity of Km of ∼ 17 mM, fructose (∼76 mM), galactose (∼92 mM) and mannose (∼125 mM) but high affinity glucosamine transporter (Km= ∼0.8 mM). The amino acid sequence of GLUT2 shows 81% resemblance among the human, rat and mouse.
In this study, a phylogenetic tree of 10 species of hominidae family including human was constructed using NCBI and Clustal Omega. Evolutionary tree shows that human GLUT2 is most closely related to that of Pongo abelli whereas is least related to GLUT2 of Bos Taurus among these ten members (Fig. 2). GLUT2 was predicted to have 12 transmembrane helices with intracellular amino and carboxyl termini in cytosol. It was also found to contain extracellular and intracellular loops which are located between the segments of 1st and 2nd transmembrane domains and between 6th and 7th transmembrane segments (Fig. 3)
The human genome consists of three billion base pairs. The SNPs neither cause disease nor indicate the sign of disease progression, but they can facilitate to establish the possibility that someone has acquired a specific disease. The SNPs build up approximately 90 of all genetic variations of human and take place every 100–300 bases on the genome (Noreen and Arshad, 2015). On a large scale genotyping and genome sequencing projects are producing huge data for the sequencing of diseased and healthy individuals. In human beings as well as in the model organisms the sequence variants are present in the genome of protein non-coding and coding regions. In non-coding regions, variants usually have no effect on gene expression and a regular function (Noreen et al., 2021). Association of molecular epidemiological studies is mainly concerned with non synonymous single nucleotide polymorphism (nsSNPs) that resides in exonic regions of gene (Savas et al., 2004; Zhu et al., 2004). Studying the structural as well as functional effect of nsSNPs on protein can facilitate in chosing nsSNPs which are functionally important. The activity and functioning of proteins are affected mainly by the coding variants in which truncation or frame shift, insertion or amino acids deletion or switching are included. There are so many variants, thus it is matter of great challenge to recognize important variants for disease. More than a dozen algorithms have been developed for resolving this issue. Some recent predicted algorithms are developed which utilize some score approaches that are alignment focused such as PolyPhen (Adzhubei et al., 2010), SIFT etc. In this study some sequences as well as structural homology focused algorithms were used to screen those SNPs which can play fundamental role in structural and functional changes in GLUT2.
The SIFT is a tool that was used to predict tolerant and intolerant amino acid substitution effect on protein function (Ng and Henikoff, 2001). It mainly considers homologous sequence alignment and physical amino acid properties to forecast possible influence of nsSNPs on protein. Out of 293 nsSNPs, 167 were forecasted to be damaging (Table 2). PolyPhen-2 (Adzhubei et al., 2010) was used to predict structural and functional influence of the nsSNPs lying in GLUT2. It considers homologous sequences and 3D structures of protein to predict the possible potential effect of SNPs on protein. Out of 293 nsSNPs, 165 were considered to be benign. 65 were predicted to be possibly damaging and 77 were considered to be probably damaging as shown in Table 2.
PROVEAN gave score to forecast neutral and deleterious effect of 293 nsSNPs present in coding region of GLUT2 protein. If the score was equal to or below −2.5 the results were deleterious and if the score was above −2.5, it was neutral. Out of 293 nsSNPs, 162 were considered to be neutral and 138 were predicted to be deleterious. It also gave the results of inframe deletion and insertion. Out of 4 inframe deletion 2 (rs772999215), (rs774721090) were found to be deleterious while others have shown no results. 3 SNPs were inframe insertion (rs1161394690), (rs1463507753), (rs749789723) and no results were found for them (Table 2).
The SNPeffect server was used to predict the effect of molecular phenotype of nsSNPs present in coding region of GLUT2. To find the effect of 293 nsSNPs on aggregation tendency, amyloid propensity and chaperon binding tendency, the dTANGO, dWALTZ and dLIMBO score was obtained. In a protein sequence, aggregation propensity was detected by dTANGO. Out of 293 nsSNPs, 61 were predicted to decrease and 27 to increase the aggregation propensity while 211 had not affect. Amyloid propensity was given by dWALTZ. 23 were expected to increase the amyloid propensity, 16 to decrease the amyloid propensity and 257 had not affect. According to dLIMBO, the chaperon binding tendency was given. None of the nsSNPs had any affecte on chaperon binding tendency (Table 3).
The recessive autosomal disease characterized by acquisition of hepatorenal glycogen, Fanconi nephropathy, galactose and improper carbohydrate utilization is FBS (Fanconi, 1949). Santer et al firstly recognized the underlying defect and GLUT2 as a possible site for the central defect, and three mutations in the GLUT2 gene have been investigated in this concern. At neucleotide 1405, the C /T transition was reported to result in production of truncated GLUT-2 protein leading to development to FBS. (Santer et al., 1997). Our rsults are in line with this study because same nsSNP is predicted to be intolerant, probably damaging and deleterious by SIFT, PolyPhen and PROVEAN respectively.
In human SLC2A2 several SNPs have been described: that are situated at the coding region rs7637863 Pro[P]/Leu[L] at position 68 and rs5400 Thr[T]/Ile[I] at 110 position. The connection of these SNPs with type 2 diabetes is contentious (Barroso et al., 2003). Since then, this “historical” GLUT2 SNP has been analyzed in several genetic studies, and incompatible conclusions were reached: the SNP Thr[T]/Ile[I] at 110 position was showed either related (Barroso et al., 2003; Burgdorf et al., 2011) or not related (Miller et al., 2001;) with a risk of type 2 diabetes. Other study finds out that, rs5400 was related with the alteration from impaired glucose tolerance to hypercholesterolemia and type 2 diabetes (Laukkanen et al., 2005). During an OGTT performed on subjects stratified according to rs5400 genotype, no variation was shown in insulin secretion (Burgdorf et al., 2011), indicates that neither insulin content nor β cell mass are affected. (Laukkanen et al., 2005). In our study rs5400 was predicted to be tolerant, benign, neutral and responsible for increased aggregation tendency by SIFT, PolyPhen, PROVEAN and dTANGO respectively. Interestingly, this GLUT2 variant was related with high sugar consumption (Eny et al., 2008), indicating a GLUT2 arbitrate mechanism of glucose sensing that could modulate intake of food and sugar preference and consequently be associated with type 2 diabetes mellitus (Mueckler, 1994).
The rs7637863 Pro[P]/Leu[L] at position 68 GLUT2 SNP transported less sugar per unit of transporter, but this characteristic did not support any homeostatic disturbance, at any rate in the physiological situation. The outcome of this study showed that no affect occurs but only SIFT predicted it to be intolerant. Mostly the SLC2A2 gene mutations associated with FBS have been examined by DNA screening. The resulting GLUT2 mutants show transport function loss although biosynthesis of protein and targeting plasma membrane that is similar to wild-type protein for both of them. The syndrome of the patients having these mutations can consequently be recognized as lack of GLUT2 transport activity. Recently, compound heterozygous SLC2A2 mutations characterized by a deletion p.153–4delLI related with a missense mutation rs121909744 Pro[P]/Arg[R] at position 417 has been associated with mild FBS (mild glucosuria) (Grünert et al., 2012). Here, they showed that substitution of leucine Pro[P]/Leu[L] at position 417 diminished transport activity (Yang and Li, 2011). SIFT, PolyPhen and PROVEAN predicted (rs121909744) to have an influence on protein structure and function but SNPeffect showed no affect. Three algorithm (SIFT, PolyPhen and PROVEAN) predicted 101 SNPs to be damaging. Our results seem helpful to those epidemiologists who are involved in large-scale population-based studies. Moreover, on basis of our in silico predictions, actual role of nsSNPs can be assured by conducting demarcated in vitro and in vivo studies.
Acknowledgement
The authors would like to thank the Research Supporting Project number (RSP-2021/97) at King Saud University for funding this study, Riyadh, Saudi Arabia.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Appendix A
Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jksus.2021.101529.
Appendix A
Supplementary data
The following are the Supplementary data to this article: