rs10498212

Variant names:

• chr2-226786559-A-T
• rs10498212
• NM_005544.3:c.*21+8430T>A

Variant summary

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

The NM_005544.3(IRS1):​c.*21+8430T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 151,814 control chromosomes in the GnomAD database, including 1,052 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 (1052 hom., cov: 30)
• Consequence: IRS1 NM_005544.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.416
• Publications: 8 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=-0.77).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.*21+8430T>A		intron_variant	Intron 1 of 1	ENST00000305123.6	NP_005535.1
IRS1	XM_047444224.1	c.*22-248T>A		intron_variant	Intron 1 of 1		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.*21+8430T>A		intron_variant	Intron 1 of 1	1	NM_005544.3	ENSP00000304895.4

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15847 AN: 151696 Hom.: 1047 Cov.: 30

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0677

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.105 AC: 15888 AN: 151814 Hom.: 1052 Cov.: 30 AF XY: 0.107 AC XY: 7928 AN XY: 74206

African (AFR) AF: 0.136 AC: 5633 AN: 41378

American (AMR) AF: 0.148 AC: 2252 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3464

East Asian (EAS) AF: 0.211 AC: 1087 AN: 5140

South Asian (SAS) AF: 0.245 AC: 1172 AN: 4788

European-Finnish (FIN) AF: 0.0303 AC: 320 AN: 10548

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0677 AC: 4602 AN: 67962

Other (OTH) AF: 0.118 AC: 247 AN: 2102

Alfa AF: 0.0813 Hom.: 81

Bravo AF: 0.114

Asia WGS AF: 0.231 AC: 801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		-0.42
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: rs10498212; hg19: chr2-227651275;