rs2435185

Variant names:

• chr2-226771707-A-G
• rs2435185
• NM_005544.3:c.*21+23282T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000305123.6(IRS1):​c.*21+23282T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 152,232 control chromosomes in the GnomAD database, including 19 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 0.014 (19 hom., cov: 32)
• Consequence: IRS1 ENST00000305123.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.369
• Publications: 4 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=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0145 (2206/152232) while in subpopulation NFE AF = 0.0227 (1542/68002). AF 95% confidence interval is 0.0217. There are 19 homozygotes in GnomAd4. There are 1063 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2206 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000305123.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	NM_005544.3	MANE Select	c.*21+23282T>C		intron	N/A	NP_005535.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	ENST00000305123.6	TSL:1 MANE Select	c.*21+23282T>C		intron	N/A	ENSP00000304895.4

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2206 AN: 152114 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0225

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

GnomAD4 genome AF: 0.0145 AC: 2206 AN: 152232 Hom.: 19 Cov.: 32 AF XY: 0.0143 AC XY: 1063 AN XY: 74438

African (AFR) AF: 0.00433 AC: 180 AN: 41546

American (AMR) AF: 0.0141 AC: 215 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1542 AN: 68002

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0227 Hom.: 50

Bravo AF: 0.0141

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.68
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism

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: rs2435185; hg19: chr2-227636423;