2-226780809-T-A

Position:

• chr2-226780809-T-A

Variant summary

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

The NM_005544.3(IRS1):​c.*21+14180A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,222 control chromosomes in the GnomAD database, including 2,073 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 0.14 (2073 hom., cov: 32)
• Consequence: IRS1 NM_005544.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.398

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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS1	NM_005544.3	c.*21+14180A>T		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+14180A>T		intron_variant		1	NM_005544.3	ENSP00000304895	P1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21748 AN: 152104 Hom.: 2067 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0744

Gnomad OTH AF: 0.135

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

GnomAD4 genome AF: 0.143 AC: 21800 AN: 152222 Hom.: 2073 Cov.: 32 AF XY: 0.144 AC XY: 10721 AN XY: 74426

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.0538

Gnomad4 NFE AF: 0.0744

Gnomad4 OTH AF: 0.136

Alfa AF: 0.111 Hom.: 177

Bravo AF: 0.159

Asia WGS AF: 0.231 AC: 800 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.24
DANN	Benign	0.83

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: rs1025333; hg19: chr2-227645525;