chr13-109776576-G-A

Position:

• chr13-109776576-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003749.3(IRS2):​c.4012+5466C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,140 control chromosomes in the GnomAD database, including 7,122 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 0.30 (7122 hom., cov: 33)
• Consequence: IRS2 NM_003749.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS2	NM_003749.3	c.4012+5466C>T		intron_variant		ENST00000375856.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS2	ENST00000375856.5	c.4012+5466C>T		intron_variant		1	NM_003749.3	P1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46159 AN: 152022 Hom.: 7123 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.326

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

GnomAD4 genome AF: 0.304 AC: 46178 AN: 152140 Hom.: 7122 Cov.: 33 AF XY: 0.304 AC XY: 22579 AN XY: 74390

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.362

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.327

Alfa AF: 0.282 Hom.: 763

Bravo AF: 0.296

Asia WGS AF: 0.289 AC: 1000 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.6
DANN	Benign	0.20

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: rs9559654; hg19: chr13-110428923;