rs4773092

Variant names:

• chr13-109783606-A-G
• rs4773092
• NM_003749.3:c.2448T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_003749.3(IRS2):​c.2448T>C​(p.Cys816Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,548,250 control chromosomes in the GnomAD database, including 267,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.60 (27103 hom., cov: 34)
  • Exomes 𝑓: 0.58 (239991 hom.)
• Consequence: IRS2 NM_003749.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.540

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 13-109783606-A-G is Benign according to our data. Variant chr13-109783606-A-G is described in ClinVar as [Benign]. Clinvar id is 3059034.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3	c.2448T>C	p.Cys816Cys	synonymous_variant	Exon 1 of 2	ENST00000375856.5	NP_003740.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS2	ENST00000375856.5	c.2448T>C	p.Cys816Cys	synonymous_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90337 AN: 151834 Hom.: 27071 Cov.: 34

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.562

GnomAD3 exomes AF: 0.587 AC: 87024 AN: 148290 Hom.: 25906 AF XY: 0.580 AC XY: 46376 AN XY: 79996

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.693

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.467

Gnomad SAS exome AF: 0.500

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.589

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.585 AC: 816240 AN: 1396298 Hom.: 239991 Cov.: 73 AF XY: 0.582 AC XY: 400698 AN XY: 687964

Gnomad4 AFR exome AF: 0.604

Gnomad4 AMR exome AF: 0.687

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.490

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.590

Gnomad4 OTH exome AF: 0.569

GnomAD4 genome AF: 0.595 AC: 90418 AN: 151952 Hom.: 27103 Cov.: 34 AF XY: 0.595 AC XY: 44184 AN XY: 74230

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.621

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.594

Gnomad4 OTH AF: 0.559

Alfa AF: 0.590 Hom.: 34524

Bravo AF: 0.601

Asia WGS AF: 0.477 AC: 1665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

IRS2-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.81
DANN	Benign	0.43

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

Other links and lift over

dbSNP: rs4773092; hg19: chr13-110435953; COSMIC: COSV65478656; COSMIC: COSV65478656;