rs2234931

Positions:

• chr2-226798037-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005544.3(IRS1):​c.702G>A​(p.Gly234=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 1,614,018 control chromosomes in the GnomAD database, including 3,345 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 0.060 (276 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3069 hom.)
• Consequence: IRS1 NM_005544.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0200

Genes affected

IRS1 (HGNC:6125): (insulin receptor substrate 1) This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-0.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS1	NM_005544.3	c.702G>A	p.Gly234=	synonymous_variant	1/2	ENST00000305123.6
IRS1	XM_047444223.1	c.702G>A	p.Gly234=	synonymous_variant	1/2
IRS1	XM_047444224.1	c.702G>A	p.Gly234=	synonymous_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS1	ENST00000305123.6	c.702G>A	p.Gly234=	synonymous_variant	1/2	1	NM_005544.3	P1

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9093 AN: 152092 Hom.: 277 Cov.: 32

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.0500

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.0205

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0665

Gnomad OTH AF: 0.0770

GnomAD3 exomes AF: 0.0519 AC: 13039 AN: 251414 Hom.: 384 AF XY: 0.0516 AC XY: 7019 AN XY: 135896

Gnomad AFR exome AF: 0.0618

Gnomad AMR exome AF: 0.0387

Gnomad ASJ exome AF: 0.0437

Gnomad EAS exome AF: 0.0140

Gnomad SAS exome AF: 0.0370

Gnomad FIN exome AF: 0.0529

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0618 AC: 90306 AN: 1461808 Hom.: 3069 Cov.: 37 AF XY: 0.0616 AC XY: 44819 AN XY: 727202

Gnomad4 AFR exome AF: 0.0623

Gnomad4 AMR exome AF: 0.0406

Gnomad4 ASJ exome AF: 0.0399

Gnomad4 EAS exome AF: 0.0204

Gnomad4 SAS exome AF: 0.0387

Gnomad4 FIN exome AF: 0.0507

Gnomad4 NFE exome AF: 0.0672

Gnomad4 OTH exome AF: 0.0569

GnomAD4 genome AF: 0.0597 AC: 9085 AN: 152210 Hom.: 276 Cov.: 32 AF XY: 0.0586 AC XY: 4363 AN XY: 74412

Gnomad4 AFR AF: 0.0623

Gnomad4 AMR AF: 0.0499

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.0203

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.0499

Gnomad4 NFE AF: 0.0665

Gnomad4 OTH AF: 0.0762

Alfa AF: 0.0662 Hom.: 463

Bravo AF: 0.0598

Asia WGS AF: 0.0310 AC: 108 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0717

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.4
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs2234931; hg19: chr2-227662753;