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. Synonymous variant affecting the same amino acid position (i.e. G234G) has been classified as Uncertain significance.

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.

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.702G>A	p.Gly234Gly	synonymous	Exon 1 of 2	NP_005535.1	P35568

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRS1	ENST00000305123.6	TSL:1 MANE Select	c.702G>A	p.Gly234Gly	synonymous	Exon 1 of 2	ENSP00000304895.4	P35568
IRS1	ENST00000918829.1		c.702G>A	p.Gly234Gly	synonymous	Exon 1 of 2	ENSP00000588888.1
ENSG00000272622	ENST00000727660.1		n.8C>T		non_coding_transcript_exon	Exon 1 of 4

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 v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over