Variant 13-109782929-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003749.3(IRS2):c.3125A>C(p.Tyr1042Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,366,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

IRS2
NM_003749.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23912397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS2	NM_003749.3 linkuse as main transcript	c.3125A>C	p.Tyr1042Ser	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.3125A>C	p.Tyr1042Ser	missense_variant	1/2	1	NM_003749.3	ENSP00000365016	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.32e-7

AC:

AN:

1366586

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

673708

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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

Feb 21, 2024

The c.3125A>C (p.Y1042S) alteration is located in exon 1 (coding exon 1) of the IRS2 gene. This alteration results from a A to C substitution at nucleotide position 3125, causing the tyrosine (Y) at amino acid position 1042 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

0.32

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.36

Eigen

Benign

-0.027

Eigen_PC

Benign

0.038

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Benign

0.46

Sift4G

Benign

0.35

Polyphen

0.65

Vest4

0.26

MutPred

0.26

Gain of glycosylation at Y1042 (P = 0.0014);

MVP

0.51

ClinPred

0.27

GERP RS

4.1

Varity_R

0.24

gMVP

0.55

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