rs41265094

Positions:

chr2-226796287-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005544.3(IRS1):c.2452G>C(p.Gly818Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,613,528 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 11 hom., cov: 33)

Exomes 𝑓: 0.012 ( 134 hom. )

Consequence

IRS1
NM_005544.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.69

Variant links:

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]

IRS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008466393).

BP6

Variant 2-226796287-C-G is Benign according to our data. Variant chr2-226796287-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 402985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-226796287-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1230 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS1	NM_005544.3 linkuse as main transcript	c.2452G>C	p.Gly818Arg	missense_variant	1/2	ENST00000305123.6	NP_005535.1	P35568
IRS1	XM_047444223.1 linkuse as main transcript	c.2452G>C	p.Gly818Arg	missense_variant	1/2		XP_047300179.1
IRS1	XM_047444224.1 linkuse as main transcript	c.2452G>C	p.Gly818Arg	missense_variant	1/2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6 linkuse as main transcript	c.2452G>C	p.Gly818Arg	missense_variant	1/2	1	NM_005544.3	ENSP00000304895.4		P35568

Frequencies

GnomAD3 genomes

AF:

0.00808

AC:

1230

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00907

GnomAD3 exomes

AF:

0.00828

AC:

2075

AN:

250672

Hom.:

AF XY:

0.00806

AC XY:

1094

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00218

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00317

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0121

AC:

17692

AN:

1461170

Hom.:

134

Cov.:

AF XY:

0.0119

AC XY:

8652

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.00347

Gnomad4 ASJ exome

AF:

0.00383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00307

Gnomad4 FIN exome

AF:

0.0203

Gnomad4 NFE exome

AF:

0.0139

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00807

AC:

1230

AN:

152358

Hom.:

Cov.:

AF XY:

0.00825

AC XY:

615

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0178

Gnomad4 NFE

AF:

0.0122

Gnomad4 OTH

AF:

0.00898

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00734

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0128

AC:

110

ExAC

AF:

0.00815

AC:

989

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	IRS1: BP4, BS1, BS2 -

Type 2 diabetes mellitus

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 17, 2014	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Has been reported in a patient with NIDDM. 2% MAF. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.5

REVEL

Benign

0.23

Sift

Benign

0.095

Sift4G

Uncertain

0.052

Polyphen

1.0

Vest4

0.64

MutPred

0.56

Gain of solvent accessibility (P = 6e-04);

MVP

0.85

MPC

1.0

ClinPred

0.012

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over