2-226796327-T-C

Position:

• chr2-226796327-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005544.3(IRS1):​c.2412A>G​(p.Ala804Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,613,290 control chromosomes in the GnomAD database, including 20,336 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 0.20 (4769 hom., cov: 33)
  • Exomes 𝑓: 0.12 (15567 hom.)
• Consequence: IRS1 NM_005544.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.31

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP7: Synonymous conserved (PhyloP=-7.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS1	NM_005544.3	c.2412A>G	p.Ala804Ala	synonymous_variant	1/2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.2412A>G	p.Ala804Ala	synonymous_variant	1/2		XP_047300179.1
IRS1	XM_047444224.1	c.2412A>G	p.Ala804Ala	synonymous_variant	1/2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.2412A>G	p.Ala804Ala	synonymous_variant	1/2	1	NM_005544.3	ENSP00000304895.4

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30985 AN: 152100 Hom.: 4746 Cov.: 33

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.0883

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.178 AC: 44542 AN: 250862 Hom.: 5720 AF XY: 0.171 AC XY: 23218 AN XY: 135712

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.262

Gnomad FIN exome AF: 0.0628

Gnomad NFE exome AF: 0.0890

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.119 AC: 173339 AN: 1461072 Hom.: 15567 Cov.: 43 AF XY: 0.122 AC XY: 88594 AN XY: 726836

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.0687

Gnomad4 NFE exome AF: 0.0839

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.204 AC: 31074 AN: 152218 Hom.: 4769 Cov.: 33 AF XY: 0.204 AC XY: 15190 AN XY: 74440

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.0585

Gnomad4 NFE AF: 0.0883

Gnomad4 OTH AF: 0.200

Alfa AF: 0.148 Hom.: 1815

Bravo AF: 0.226

Asia WGS AF: 0.279 AC: 968 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.052
DANN	Benign	0.27

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: rs1801123; hg19: chr2-227661043; COSMIC: COSV59337490; COSMIC: COSV59337490;