13-109781963-G-T

Variant names:

• chr13-109781963-G-T
• rs11618950
• NM_003749.3:c.4012+79C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003749.3(IRS2):​c.4012+79C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,426 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: IRS2 NM_003749.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.875
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3	c.4012+79C>A		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+79C>A		intron_variant	Intron 1 of 1	1	NM_003749.3	ENSP00000365016.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1357426 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 673674

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31776

American (AMR) AF: 0.00 AC: 0 AN: 37030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24888

East Asian (EAS) AF: 0.00 AC: 0 AN: 37998

South Asian (SAS) AF: 0.00 AC: 0 AN: 80228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5414

European-Non Finnish (NFE) AF: 9.63e-7 AC: 1 AN: 1038454

Other (OTH) AF: 0.00 AC: 0 AN: 56894

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.45
DANN	Benign	0.38
PhyloP100		-0.88

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: rs11618950; hg19: chr13-110434310;