2-226795828-C-T

Variant names:

• chr2-226795828-C-T
• rs1801278
• NM_005544.3:c.2911G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_005544.3(IRS1):​c.2911G>A​(p.Gly971Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,613,026 control chromosomes in the GnomAD database, including 3,374 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.060 (278 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3096 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.972
• Publications: 484 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 (MetaRNN=0.0019664168).
• BP6: Variant 2-226795828-C-T is Benign according to our data. Variant chr2-226795828-C-T is described in ClinVar as Benign. ClinVar VariationId is 29761.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0651 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	NM_005544.3	MANE Select	c.2911G>A	p.Gly971Arg	missense	Exon 1 of 2	NP_005535.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	ENST00000305123.6	TSL:1 MANE Select	c.2911G>A	p.Gly971Arg	missense	Exon 1 of 2	ENSP00000304895.4
	IRS1	ENST00000918829.1		c.2911G>A	p.Gly971Arg	missense	Exon 1 of 2	ENSP00000588888.1
	ENSG00000272622	ENST00000727655.1		n.39C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9127 AN: 152192 Hom.: 279 Cov.: 33

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.0425

Gnomad FIN AF: 0.0504

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0668

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.0520 AC: 13009 AN: 250112 AF XY: 0.0517

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.0387

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0139

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.0651

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0620 AC: 90552 AN: 1460716 Hom.: 3096 Cov.: 44 AF XY: 0.0618 AC XY: 44921 AN XY: 726620

African (AFR) AF: 0.0626 AC: 2094 AN: 33474

American (AMR) AF: 0.0406 AC: 1815 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0400 AC: 1044 AN: 26130

East Asian (EAS) AF: 0.0204 AC: 808 AN: 39694

South Asian (SAS) AF: 0.0387 AC: 3340 AN: 86252

European-Finnish (FIN) AF: 0.0507 AC: 2666 AN: 52562

Middle Eastern (MID) AF: 0.0503 AC: 290 AN: 5768

European-Non Finnish (NFE) AF: 0.0675 AC: 75056 AN: 1111756

Other (OTH) AF: 0.0570 AC: 3439 AN: 60360

GnomAD4 genome AF: 0.0599 AC: 9120 AN: 152310 Hom.: 278 Cov.: 33 AF XY: 0.0588 AC XY: 4377 AN XY: 74484

African (AFR) AF: 0.0624 AC: 2593 AN: 41568

American (AMR) AF: 0.0502 AC: 769 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3472

East Asian (EAS) AF: 0.0201 AC: 104 AN: 5180

South Asian (SAS) AF: 0.0421 AC: 203 AN: 4822

European-Finnish (FIN) AF: 0.0504 AC: 535 AN: 10622

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0667 AC: 4539 AN: 68016

Other (OTH) AF: 0.0766 AC: 162 AN: 2116

Alfa AF: 0.0630 Hom.: 540

Bravo AF: 0.0599

TwinsUK AF: 0.0666 AC: 247

ALSPAC AF: 0.0638 AC: 246

ESP6500AA AF: 0.0579 AC: 255

ESP6500EA AF: 0.0658 AC: 566

ExAC AF: 0.0525 AC: 6376

Asia WGS AF: 0.0300 AC: 106 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0718

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Insulin resistance, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.97
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.71	P
Vest4		0.28
MutPred		0.089		Gain of MoRF binding (P = 0.0115)
MPC		1.0
ClinPred		0.030	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.44
Mutation Taster		=99/1	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: rs1801278; hg19: chr2-227660544; COSMIC: COSV59335677; COSMIC: COSV59335677;