chr2-226795828-C-T
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_005544.3(IRS1):c.2911G>A(p.Gly971Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,613,026 control chromosomes in the GnomAD database, including 3,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).
Frequency
Genomes: 𝑓 0.060 ( 278 hom., cov: 33)
Exomes 𝑓: 0.062 ( 3096 hom. )
Consequence
IRS1
NM_005544.3 missense
NM_005544.3 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 0.972
Genes affected
IRS1 (HGNC:6125): (insulin receptor substrate 1) This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0019664168).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IRS1 | NM_005544.3 | c.2911G>A | p.Gly971Arg | missense_variant | 1/2 | ENST00000305123.6 | |
IRS1 | XM_047444223.1 | c.2911G>A | p.Gly971Arg | missense_variant | 1/2 | ||
IRS1 | XM_047444224.1 | c.2911G>A | p.Gly971Arg | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IRS1 | ENST00000305123.6 | c.2911G>A | p.Gly971Arg | missense_variant | 1/2 | 1 | NM_005544.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0600 AC: 9127AN: 152192Hom.: 279 Cov.: 33
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GnomAD3 exomes AF: 0.0520 AC: 13009AN: 250112Hom.: 386 AF XY: 0.0517 AC XY: 7011AN XY: 135558
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GnomAD4 exome AF: 0.0620 AC: 90552AN: 1460716Hom.: 3096 Cov.: 44 AF XY: 0.0618 AC XY: 44921AN XY: 726620
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GnomAD4 genome AF: 0.0599 AC: 9120AN: 152310Hom.: 278 Cov.: 33 AF XY: 0.0588 AC XY: 4377AN XY: 74484
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TwinsUK
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247
ALSPAC
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246
ESP6500AA
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255
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ClinVar
Significance: risk factor
Submissions summary: Other:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Coronary artery disease, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
Insulin resistance, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
P
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of MoRF binding (P = 0.0115);
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at