rs12853546

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr13-109783567-G-A
• chr13-109783567-G-C

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

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 id 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

Gnomad4 AFR exome AF: 0.202 AC: 6390 AN: 31630

Gnomad4 AMR exome AF: 0.167 AC: 5975 AN: 35860

Gnomad4 ASJ exome AF: 0.239 AC: 5978 AN: 25060

Gnomad4 EAS exome AF: 0.188 AC: 6731 AN: 35810

Gnomad4 SAS exome AF: 0.300 AC: 23773 AN: 79194

Gnomad4 FIN exome AF: 0.236 AC: 11250 AN: 47690

Gnomad4 NFE exome AF: 0.247 AC: 266692 AN: 1078330

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.199 AC: 0.198762 AN: 0.198762

Gnomad4 AMR AF: 0.201 AC: 0.200771 AN: 0.200771

Gnomad4 ASJ AF: 0.245 AC: 0.245245 AN: 0.245245

Gnomad4 EAS AF: 0.222 AC: 0.221551 AN: 0.221551

Gnomad4 SAS AF: 0.294 AC: 0.294447 AN: 0.294447

Gnomad4 FIN AF: 0.242 AC: 0.241558 AN: 0.241558

Gnomad4 NFE AF: 0.242 AC: 0.24172 AN: 0.24172

Gnomad4 OTH AF: 0.259 AC: 0.258996 AN: 0.258996

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
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

Publications

LitVar

Other links and lift over

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