Variant chr13-109782129-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000375856.5(IRS2):c.3925C>T(p.Pro1309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,607,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

IRS2
ENST00000375856.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.68

Variant links:

Genes affected

IRS2 (HGNC:6126): (insulin receptor substrate 2) This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment. [provided by RefSeq, Jul 2008]

IRS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03095758).

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS2	NM_003749.3 linkuse as main transcript	c.3925C>T	p.Pro1309Ser	missense_variant	1/2	ENST00000375856.5	NP_003740.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS2	ENST00000375856.5 linkuse as main transcript	c.3925C>T	p.Pro1309Ser	missense_variant	1/2	1	NM_003749.3	ENSP00000365016	P1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000162

AC:

AN:

228166

Hom.:

AF XY:

0.000158

AC XY:

AN XY:

126402

show subpopulations

Gnomad AFR exome

AF:

0.00196

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000234

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000701

AC:

102

AN:

1455716

Hom.:

Cov.:

AF XY:

0.0000829

AC XY:

AN XY:

723860

show subpopulations

Gnomad4 AFR exome

AF:

0.00189

Gnomad4 AMR exome

AF:

0.0000906

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.000200

GnomAD4 genome

AF:

0.000545

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000737

ESP6500AA

AF:

0.000731

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000172

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.3925C>T (p.P1309S) alteration is located in exon 1 (coding exon 1) of the IRS2 gene. This alteration results from a C to T substitution at nucleotide position 3925, causing the proline (P) at amino acid position 1309 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.65

M_CAP

Benign

0.057

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.93

REVEL

Benign

0.056

Sift

Benign

0.034

Sift4G

Benign

0.53

Polyphen

0.63

Vest4

0.40

MVP

0.42

ClinPred

0.030

GERP RS

4.2

Varity_R

0.061

gMVP

0.45

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