2-226732872-A-G

Position:

• chr2-226732872-A-G

Variant summary

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

The NM_005544.3(IRS1):​c.*3400T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,112 control chromosomes in the GnomAD database, including 1,204 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 0.10 (1204 hom., cov: 32)
  • Exomes 𝑓: 0.083 (0 hom.)
• Consequence: IRS1 NM_005544.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS1	NM_005544.3	c.*3400T>C		3_prime_UTR_variant	2/2	ENST00000305123.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS1	ENST00000305123.6	c.*3400T>C		3_prime_UTR_variant	2/2	1	NM_005544.3	P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15773 AN: 151982 Hom.: 1199 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.0848

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.0895

GnomAD4 exome AF: 0.0833 AC: 1 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 1 AN XY: 8

Gnomad4 AFR exome AF: 0.00

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.104 AC: 15814 AN: 152100 Hom.: 1204 Cov.: 32 AF XY: 0.104 AC XY: 7720 AN XY: 74370

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.0937

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0175

Gnomad4 NFE AF: 0.0485

Gnomad4 OTH AF: 0.0885

Alfa AF: 0.0840 Hom.: 161

Bravo AF: 0.120

Asia WGS AF: 0.150 AC: 519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.16
DANN	Benign	0.29

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: rs13431554; hg19: chr2-227597588;