Genetic Variant NM_005544.3:c.702G>A (chr2-226798037-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_005544.3(IRS1):c.702G>A(p.Gly234Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 1,614,018 control chromosomes in the GnomAD database, including 3,345 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 0.060 ( 276 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3069 hom. )

Consequence

IRS1
NM_005544.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0200

Publications

18 publications found

Variant links:

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]

IRS1 links:

ENSG00000272622 (HGNC:):

ENSG00000272622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP7

Synonymous conserved (PhyloP=-0.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3 link	c.702G>A	p.Gly234Gly	synonymous_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1	P35568
IRS1	XM_047444223.1 link	c.702G>A	p.Gly234Gly	synonymous_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1 link	c.702G>A	p.Gly234Gly	synonymous_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6 link	c.702G>A	p.Gly234Gly	synonymous_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4		P35568

Frequencies

GnomAD3 genomes

AF:

0.0598

AC:

9093

AN:

152092

Hom.:

277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0625

Gnomad AMI

AF:

0.0473

Gnomad AMR

AF:

0.0500

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.0205

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.0499

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0665

Gnomad OTH

AF:

0.0770

GnomAD2 exomes

AF:

0.0519

AC:

13039

AN:

251414

AF XY:

0.0516

show subpopulations

Gnomad AFR exome

AF:

0.0618

Gnomad AMR exome

AF:

0.0387

Gnomad ASJ exome

AF:

0.0437

Gnomad EAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.0529

Gnomad NFE exome

AF:

0.0649

Gnomad OTH exome

AF:

0.0564

GnomAD4 exome

AF:

0.0618

AC:

90306

AN:

1461808

Hom.:

3069

Cov.:

AF XY:

0.0616

AC XY:

44819

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0623

AC:

2086

AN:

33480

American (AMR)

AF:

0.0406

AC:

1816

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0399

AC:

1044

AN:

26136

East Asian (EAS)

AF:

0.0204

AC:

810

AN:

39700

South Asian (SAS)

AF:

0.0387

AC:

3337

AN:

86258

European-Finnish (FIN)

AF:

0.0507

AC:

2703

AN:

53350

Middle Eastern (MID)

AF:

0.0505

AC:

291

AN:

5768

European-Non Finnish (NFE)

AF:

0.0672

AC:

74780

AN:

1112000

Other (OTH)

AF:

0.0569

AC:

3439

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

5644

11288

16933

22577

28221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2754

5508

8262

11016

13770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0597

AC:

9085

AN:

152210

Hom.:

276

Cov.:

AF XY:

0.0586

AC XY:

4363

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0623

AC:

2588

AN:

41538

American (AMR)

AF:

0.0499

AC:

763

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

151

AN:

3472

East Asian (EAS)

AF:

0.0203

AC:

105

AN:

5168

South Asian (SAS)

AF:

0.0419

AC:

202

AN:

4824

European-Finnish (FIN)

AF:

0.0499

AC:

529

AN:

10604

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0665

AC:

4522

AN:

67992

Other (OTH)

AF:

0.0762

AC:

161

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

438

877

1315

1754

2192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0646

Hom.:

585

Bravo

AF:

0.0598

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0717

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.4

(source)

DANN

Benign

0.92

PhyloP100

-0.020

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over