13-109783567-G-A

Variant names:

• chr13-109783567-G-A
• rs12853546
• NM_003749.3:c.2487C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_003749.3(IRS2):​c.2487C>T​(p.Pro829Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,549,162 control chromosomes in the GnomAD database, including 47,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (4035 hom., cov: 34)
  • Exomes 𝑓: 0.25 (43363 hom.)
• Consequence: IRS2 NM_003749.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.75
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-109783567-G-A is Benign according to our data. Variant chr13-109783567-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056733.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-3.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3	c.2487C>T	p.Pro829Pro	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.2487C>T	p.Pro829Pro	synonymous_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34661 AN: 151992 Hom.: 4037 Cov.: 34

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.258

GnomAD2 exomes AF: 0.236 AC: 33798 AN: 143350 AF XY: 0.242

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.246 AC: 344112 AN: 1397052 Hom.: 43363 Cov.: 77 AF XY: 0.248 AC XY: 170615 AN XY: 688968

African (AFR) AF: 0.202 AC: 6390 AN: 31630

American (AMR) AF: 0.167 AC: 5975 AN: 35860

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 5978 AN: 25060

East Asian (EAS) AF: 0.188 AC: 6731 AN: 35810

South Asian (SAS) AF: 0.300 AC: 23773 AN: 79194

European-Finnish (FIN) AF: 0.236 AC: 11250 AN: 47690

Middle Eastern (MID) AF: 0.418 AC: 2332 AN: 5578

European-Non Finnish (NFE) AF: 0.247 AC: 266692 AN: 1078330

Other (OTH) AF: 0.259 AC: 14991 AN: 57900

GnomAD4 genome AF: 0.228 AC: 34668 AN: 152110 Hom.: 4035 Cov.: 34 AF XY: 0.228 AC XY: 16917 AN XY: 74336

African (AFR) AF: 0.199 AC: 8255 AN: 41532

American (AMR) AF: 0.201 AC: 3071 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 851 AN: 3470

East Asian (EAS) AF: 0.222 AC: 1137 AN: 5132

South Asian (SAS) AF: 0.294 AC: 1421 AN: 4826

European-Finnish (FIN) AF: 0.242 AC: 2561 AN: 10602

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16422 AN: 67938

Other (OTH) AF: 0.259 AC: 547 AN: 2112

Alfa AF: 0.200 Hom.: 1030

Bravo AF: 0.223

Asia WGS AF: 0.250 AC: 868 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

IRS2-related disorder Benign:1

Oct 18, 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	-0.80
CADD	Benign	2.6
DANN	Benign	0.87
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12853546; hg19: chr13-110435914; COSMIC: COSV65477043; COSMIC: COSV65477043;