rs9583424

chr13-109782955-T-Cchr13-109782955-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003749.3(IRS2):c.3099A>G(p.Pro1033=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,417,628 control chromosomes in the GnomAD database, including 45,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8318 hom., cov: 32)
  • Exomes 𝑓: 0.24 (37149 hom.)
• Consequence: IRS2 NM_003749.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 13-109782955-T-C is Benign according to our data. Variant chr13-109782955-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 768633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS2	NM_003749.3	c.3099A>G	p.Pro1033=	synonymous_variant	1/2	ENST00000375856.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS2	ENST00000375856.5	c.3099A>G	p.Pro1033=	synonymous_variant	1/2	1	NM_003749.3	P1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 46764 AN: 150610 Hom.: 8299 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.195

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.265

GnomAD3 exomes AF: 0.172 AC: 8620 AN: 50236 Hom.: 806 AF XY: 0.173 AC XY: 4995 AN XY: 28816

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.0898

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.0207

Gnomad SAS exome AF: 0.149

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.241 AC: 304951 AN: 1266904 Hom.: 37149 Cov.: 50 AF XY: 0.239 AC XY: 148452 AN XY: 620728

Gnomad4 AFR exome AF: 0.479

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.0756

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.268

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.311 AC: 46833 AN: 150724 Hom.: 8318 Cov.: 32 AF XY: 0.308 AC XY: 22640 AN XY: 73612

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.0627

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.263

Alfa AF: 0.293 Hom.: 715

Bravo AF: 0.314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IRS2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.27
Dann	Benign	0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs9583424; hg19: chr13-110435302; COSMIC: COSV65478240; COSMIC: COSV65478240;