2-226773047-A-T

Position:

• chr2-226773047-A-T

Variant summary

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

The NM_005544.3(IRS1):​c.*21+21942T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,200 control chromosomes in the GnomAD database, including 2,790 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 0.16 (2790 hom., cov: 32)
• Consequence: IRS1 NM_005544.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS1	NM_005544.3	c.*21+21942T>A		intron_variant		ENST00000305123.6	NP_005535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.*21+21942T>A		intron_variant		1	NM_005544.3	ENSP00000304895.4

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24267 AN: 152082 Hom.: 2776 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0555

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.160 AC: 24336 AN: 152200 Hom.: 2790 Cov.: 32 AF XY: 0.160 AC XY: 11923 AN XY: 74410

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.0555

Gnomad4 NFE AF: 0.0718

Gnomad4 OTH AF: 0.142

Alfa AF: 0.119 Hom.: 220

Bravo AF: 0.178

Asia WGS AF: 0.238 AC: 826 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.62
DANN	Benign	0.55

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: rs4675093; hg19: chr2-227637763;