dbSNP rs4773092: IRS2:p.Cys816Cys (chr13-109783606-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_003749.3(IRS2):c.2448T>C(p.Cys816Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,548,250 control chromosomes in the GnomAD database, including 267,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.60 ( 27103 hom., cov: 34)

Exomes 𝑓: 0.58 ( 239991 hom. )

Consequence

IRS2
NM_003749.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.540

Publications

39 publications found

Variant links:

Genes affected

IRS2 (HGNC:6126): (insulin receptor substrate 2) This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment. [provided by RefSeq, Jul 2008]

IRS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 13-109783606-A-G is Benign according to our data. Variant chr13-109783606-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059034.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.2448T>C	p.Cys816Cys	synonymous_variant	Exon 1 of 2	ENST00000375856.5	NP_003740.2	Q9Y4H2Q9P084

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS2	ENST00000375856.5 link	c.2448T>C	p.Cys816Cys	synonymous_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90337

AN:

151834

Hom.:

27071

Cov.:

show subpopulations

Gnomad AFR

AF:

0.606

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.651

Gnomad ASJ

AF:

0.621

Gnomad EAS

AF:

0.449

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.604

Gnomad MID

AF:

0.474

Gnomad NFE

AF:

0.594

Gnomad OTH

AF:

0.562

GnomAD2 exomes

AF:

0.587

AC:

87024

AN:

148290

AF XY:

0.580

show subpopulations

Gnomad AFR exome

AF:

0.602

Gnomad AMR exome

AF:

0.693

Gnomad ASJ exome

AF:

0.617

Gnomad EAS exome

AF:

0.467

Gnomad FIN exome

AF:

0.607

Gnomad NFE exome

AF:

0.589

Gnomad OTH exome

AF:

0.569

GnomAD4 exome

AF:

0.585

AC:

816240

AN:

1396298

Hom.:

239991

Cov.:

AF XY:

0.582

AC XY:

400698

AN XY:

687964

show subpopulations

African (AFR)

AF:

0.604

AC:

19147

AN:

31690

American (AMR)

AF:

0.687

AC:

24758

AN:

36024

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

15437

AN:

25026

East Asian (EAS)

AF:

0.490

AC:

17622

AN:

35930

South Asian (SAS)

AF:

0.503

AC:

39952

AN:

79382

European-Finnish (FIN)

AF:

0.609

AC:

29163

AN:

47880

Middle Eastern (MID)

AF:

0.425

AC:

2398

AN:

5644

European-Non Finnish (NFE)

AF:

0.590

AC:

634881

AN:

1076918

Other (OTH)

AF:

0.569

AC:

32882

AN:

57804

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

21337

42674

64010

85347

106684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17650

35300

52950

70600

88250

<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:

0.595

AC:

90418

AN:

151952

Hom.:

27103

Cov.:

AF XY:

0.595

AC XY:

44184

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.606

AC:

25147

AN:

41500

American (AMR)

AF:

0.652

AC:

9966

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.621

AC:

2155

AN:

3472

East Asian (EAS)

AF:

0.448

AC:

2284

AN:

5098

South Asian (SAS)

AF:

0.501

AC:

2413

AN:

4820

European-Finnish (FIN)

AF:

0.604

AC:

6385

AN:

10576

Middle Eastern (MID)

AF:

0.469

AC:

136

AN:

290

European-Non Finnish (NFE)

AF:

0.594

AC:

40288

AN:

67878

Other (OTH)

AF:

0.559

AC:

1181

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1957

3914

5870

7827

9784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

752

1504

2256

3008

3760

<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:

0.589

Hom.:

41573

Bravo

AF:

0.601

Asia WGS

AF:

0.477

AC:

1665

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IRS2-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.81

(source)

DANN

Benign

0.43

PhyloP100

-0.54

Mutation Taster

=100/0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over