rs9653366

Variant names:

• chr2-226739948-G-A
• rs9653366
• NM_005544.3:c.*22-3698C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005544.3(IRS1):​c.*22-3698C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 152,304 control chromosomes in the GnomAD database, including 482 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 0.066 (482 hom., cov: 33)
• Consequence: IRS1 NM_005544.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.*22-3698C>T		intron_variant	Intron 1 of 1	ENST00000305123.6	NP_005535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.*22-3698C>T		intron_variant	Intron 1 of 1	1	NM_005544.3	ENSP00000304895.4

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 10122 AN: 152186 Hom.: 485 Cov.: 33

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0881

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0471

Gnomad OTH AF: 0.0636

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

GnomAD4 genome AF: 0.0665 AC: 10124 AN: 152304 Hom.: 482 Cov.: 33 AF XY: 0.0670 AC XY: 4989 AN XY: 74478

African (AFR) AF: 0.0656 AC: 2726 AN: 41570

American (AMR) AF: 0.119 AC: 1816 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0881 AC: 306 AN: 3472

East Asian (EAS) AF: 0.189 AC: 979 AN: 5182

South Asian (SAS) AF: 0.139 AC: 672 AN: 4826

European-Finnish (FIN) AF: 0.0173 AC: 184 AN: 10614

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0471 AC: 3206 AN: 68018

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0592 Hom.: 84

Bravo AF: 0.0770

Asia WGS AF: 0.137 AC: 476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.8
DANN	Benign	0.57
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9653366; hg19: chr2-227604664;