2-226795330-C-T

Variant names:

• chr2-226795330-C-T
• rs3731594
• NM_005544.3:c.3409G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005544.3(IRS1):​c.3409G>A​(p.Asp1137Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,520 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (71 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028790236).
• BP6: Variant 2-226795330-C-T is Benign according to our data. Variant chr2-226795330-C-T is described in ClinVar as [Benign]. Clinvar id is 770879.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.3409G>A	p.Asp1137Asn	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.3409G>A	p.Asp1137Asn	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.3409G>A	p.Asp1137Asn	missense_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.3409G>A	p.Asp1137Asn	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4
ENSG00000272622	ENST00000727652.1	n.166+490C>T		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1	n.71+387C>T		intron_variant	Intron 1 of 3
IRS1	ENST00000498335.1	n.-84G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152224 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00439 AC: 1102 AN: 250816 AF XY: 0.00389

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0591

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00160 AC: 2338 AN: 1461178 Hom.: 71 Cov.: 42 AF XY: 0.00150 AC XY: 1087 AN XY: 726902

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0541 AC: 2146 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112002

Other (OTH) AF: 0.00252 AC: 152 AN: 60382

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152342 Hom.: 7 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74500

African (AFR) AF: 0.000216 AC: 9 AN: 41582

American (AMR) AF: 0.00137 AC: 21 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0550 AC: 285 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00120 Hom.: 6

Bravo AF: 0.00229

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00437 AC: 531

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	L
PhyloP100		1.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Benign	0.52	T
Polyphen		0.082	B
Vest4		0.11
MVP		0.69
MPC		0.33
ClinPred		0.0088	T
GERP RS		4.9
Varity_R		0.095
gMVP		0.17
Mutation Taster		=97/3	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: rs3731594; hg19: chr2-227660046;