13-109782884-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003749.3(IRS2):c.3170G>A(p.Gly1057Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,562,240 control chromosomes in the GnomAD database, including 86,943 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (7081 hom., cov: 32)
  • Exomes 𝑓: 0.33 (79862 hom.)
• Consequence: IRS2 NM_003749.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.425

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 (MetaRNN=3.8087368E-4).
• BP6: Variant 13-109782884-C-T is Benign according to our data. Variant chr13-109782884-C-T is described in ClinVar as [Benign]. Clinvar id is 8820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS2	NM_003749.3	c.3170G>A	p.Gly1057Asp	missense_variant	1/2	ENST00000375856.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS2	ENST00000375856.5	c.3170G>A	p.Gly1057Asp	missense_variant	1/2	1	NM_003749.3	P1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43522 AN: 151442 Hom.: 7078 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.350 AC: 54931 AN: 156960 Hom.: 10029 AF XY: 0.345 AC XY: 29439 AN XY: 85284

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.401

Gnomad SAS exome AF: 0.279

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.332 AC: 469031 AN: 1410682 Hom.: 79862 Cov.: 54 AF XY: 0.331 AC XY: 230790 AN XY: 696988

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.407

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.335

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.287 AC: 43535 AN: 151558 Hom.: 7081 Cov.: 32 AF XY: 0.291 AC XY: 21534 AN XY: 74054

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.390

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.294

Alfa AF: 0.330 Hom.: 5352

Bravo AF: 0.287

TwinsUK AF: 0.331 AC: 1228

ALSPAC AF: 0.335 AC: 1292

ESP6500AA AF: 0.117 AC: 464

ESP6500EA AF: 0.290 AC: 2312

ExAC AF: 0.264 AC: 27791

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

IRS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

DIABETES, TYPE II, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Oct 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.92
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.00038	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.052
Sift	Benign	0.22	T
Sift4G	Benign	0.33	T
Polyphen		0.089	B
Vest4		0.048
ClinPred		0.0068	T
GERP RS		2.1
Varity_R		0.033
gMVP		0.37

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: rs1805097; hg19: chr13-110435231; COSMIC: COSV65478662; COSMIC: COSV65478662;