NM_003749.3:c.4012+7180T>G

Variant names:

• chr13-109774862-A-C
• rs4771647
• NM_003749.3:c.4012+7180T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003749.3(IRS2):​c.4012+7180T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 152,064 control chromosomes in the GnomAD database, including 8,458 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8458 hom., cov: 32)
• Consequence: IRS2 NM_003749.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.164
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3	c.4012+7180T>G		intron_variant	Intron 1 of 1	ENST00000375856.5	NP_003740.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS2	ENST00000375856.5	c.4012+7180T>G		intron_variant	Intron 1 of 1	1	NM_003749.3	ENSP00000365016.3

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50306 AN: 151946 Hom.: 8460 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.365

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.331 AC: 50320 AN: 152064 Hom.: 8458 Cov.: 32 AF XY: 0.330 AC XY: 24543 AN XY: 74334

African (AFR) AF: 0.330 AC: 13686 AN: 41472

American (AMR) AF: 0.280 AC: 4286 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1176 AN: 3472

East Asian (EAS) AF: 0.239 AC: 1237 AN: 5174

South Asian (SAS) AF: 0.383 AC: 1847 AN: 4820

European-Finnish (FIN) AF: 0.365 AC: 3844 AN: 10544

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 23007 AN: 67982

Other (OTH) AF: 0.365 AC: 770 AN: 2108

Alfa AF: 0.334 Hom.: 33278

Bravo AF: 0.324

Asia WGS AF: 0.316 AC: 1096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		-0.16
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: rs4771647; hg19: chr13-110427209;