2-226773047-A-T

Variant names:

• chr2-226773047-A-T
• rs4675093
• NM_005544.3:c.*21+21942T>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+21942T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,200 control chromosomes in the GnomAD database, including 2,790 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 0.16 (2790 hom., cov: 32)
• Consequence: IRS1 NM_005544.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 5 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 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.*21+21942T>A		intron	N/A	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.*21+21942T>A		intron	N/A	ENSP00000304895.4	P35568

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24267 AN: 152082 Hom.: 2776 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0555

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.160 AC: 24336 AN: 152200 Hom.: 2790 Cov.: 32 AF XY: 0.160 AC XY: 11923 AN XY: 74410

African (AFR) AF: 0.307 AC: 12744 AN: 41484

American (AMR) AF: 0.192 AC: 2930 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 453 AN: 3472

East Asian (EAS) AF: 0.253 AC: 1307 AN: 5174

South Asian (SAS) AF: 0.218 AC: 1050 AN: 4824

European-Finnish (FIN) AF: 0.0555 AC: 589 AN: 10622

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0718 AC: 4881 AN: 68008

Other (OTH) AF: 0.142 AC: 300 AN: 2114

Alfa AF: 0.119 Hom.: 220

Bravo AF: 0.178

Asia WGS AF: 0.238 AC: 826 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.62
DANN	Benign	0.55
PhyloP100		-1.3
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: rs4675093; hg19: chr2-227637763;