2-226795099-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005544.3(IRS1):c.3640G>A(p.Gly1214Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000426 in 1,197,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1214R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000064 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

IRS1
NM_005544.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.692

Publications

0 publications found

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:

ENSG00000272622 (HGNC:):

ENSG00000272622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022031307).

BP6

Variant 2-226795099-C-T is Benign according to our data. Variant chr2-226795099-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3861297.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3 link	c.3640G>A	p.Gly1214Ser	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1	P35568
IRS1	XM_047444223.1 link	c.3640G>A	p.Gly1214Ser	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1 link	c.3640G>A	p.Gly1214Ser	missense_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRS1	ENST00000305123.6 link	c.3640G>A	p.Gly1214Ser	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4	P35568
IRS1	ENST00000498335.1 link	n.148G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
ENSG00000272622	ENST00000727652.1 link	n.166+259C>T		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1 link	n.71+156C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000643

AC:

AN:

124494

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000689

AC:

AN:

246562

AF XY:

0.0000595

show subpopulations

Gnomad AFR exome

AF:

0.000325

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000727

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000401

AC:

AN:

1073272

Hom.:

Cov.:

AF XY:

0.0000352

AC XY:

AN XY:

539312

show subpopulations

African (AFR)

AF:

0.000569

AC:

AN:

24616

American (AMR)

AF:

0.0000255

AC:

AN:

39272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18752

East Asian (EAS)

AF:

0.0000427

AC:

AN:

23424

South Asian (SAS)

AF:

0.0000250

AC:

AN:

79860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4416

European-Non Finnish (NFE)

AF:

0.0000274

AC:

AN:

803302

Other (OTH)

AF:

0.0000708

AC:

AN:

42376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000642

AC:

AN:

124538

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

58640

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

33106

American (AMR)

AF:

0.00

AC:

AN:

11008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3212

East Asian (EAS)

AF:

0.00

AC:

AN:

3492

South Asian (SAS)

AF:

0.00

AC:

AN:

3316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61278

Other (OTH)

AF:

0.00

AC:

AN:

1702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000474

Hom.:

ExAC

AF:

0.0000660

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 17, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.3

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.36

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.51

M_CAP

Benign

0.0059

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.28

PhyloP100

-0.69

PrimateAI

Benign

0.29

PROVEAN

Benign

0.38

REVEL

Benign

0.058

Sift

Benign

0.98

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.039

MutPred

0.18

Gain of phosphorylation at G1214 (P = 0.0037);

MVP

0.43

MPC

0.26

ClinPred

0.0070

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

2-226795099-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over