chr2-226796327-T-C

Variant names:

• chr2-226796327-T-C
• rs1801123
• NM_005544.3:c.2412A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 47 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]

ENSG00000272622 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005544.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	NM_005544.3	MANE Select	c.2412A>G	p.Ala804Ala	synonymous	Exon 1 of 2	NP_005535.1	P35568

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	ENST00000305123.6	TSL:1 MANE Select	c.2412A>G	p.Ala804Ala	synonymous	Exon 1 of 2	ENSP00000304895.4	P35568
	IRS1	ENST00000918829.1		c.2412A>G	p.Ala804Ala	synonymous	Exon 1 of 2	ENSP00000588888.1
	ENSG00000272622	ENST00000727653.1		n.116T>C		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.178 AC: 44542 AN: 250862 AF XY: 0.171

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 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

African (AFR) AF: 0.432 AC: 14477 AN: 33480

American (AMR) AF: 0.310 AC: 13844 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 5003 AN: 26136

East Asian (EAS) AF: 0.259 AC: 10290 AN: 39700

South Asian (SAS) AF: 0.264 AC: 22741 AN: 86258

European-Finnish (FIN) AF: 0.0687 AC: 3613 AN: 52616

Middle Eastern (MID) AF: 0.199 AC: 1146 AN: 5768

European-Non Finnish (NFE) AF: 0.0839 AC: 93282 AN: 1112002

Other (OTH) AF: 0.148 AC: 8943 AN: 60388

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

African (AFR) AF: 0.416 AC: 17268 AN: 41516

American (AMR) AF: 0.224 AC: 3428 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3468

East Asian (EAS) AF: 0.251 AC: 1297 AN: 5168

South Asian (SAS) AF: 0.264 AC: 1274 AN: 4824

European-Finnish (FIN) AF: 0.0585 AC: 621 AN: 10620

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.0883 AC: 6007 AN: 68008

Other (OTH) AF: 0.200 AC: 422 AN: 2112

Alfa AF: 0.165 Hom.: 4704

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.052
DANN	Benign	0.27
PhyloP100		-7.3
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: rs1801123; hg19: chr2-227661043; COSMIC: COSV59337490; COSMIC: COSV59337490;