dbSNP rs3742210: IRS2:p.Ser723Ser (chr13-109783885-G-A) – 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.2169C>T(p.Ser723Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,548,092 control chromosomes in the GnomAD database, including 263,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.59 ( 26532 hom., cov: 33)

Exomes 𝑓: 0.58 ( 236747 hom. )

Consequence

IRS2
NM_003749.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.01

Publications

24 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=-0.78).

BP6

Variant 13-109783885-G-A is Benign according to our data. Variant chr13-109783885-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060213.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.2169C>T	p.Ser723Ser	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.2169C>T	p.Ser723Ser	synonymous_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.589

AC:

89319

AN:

151768

Hom.:

26502

Cov.:

show subpopulations

Gnomad AFR

AF:

0.592

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.649

Gnomad ASJ

AF:

0.620

Gnomad EAS

AF:

0.448

Gnomad SAS

AF:

0.495

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.590

Gnomad OTH

AF:

0.557

GnomAD2 exomes

AF:

0.584

AC:

82284

AN:

140836

AF XY:

0.576

show subpopulations

Gnomad AFR exome

AF:

0.589

Gnomad AMR exome

AF:

0.692

Gnomad ASJ exome

AF:

0.617

Gnomad EAS exome

AF:

0.467

Gnomad FIN exome

AF:

0.604

Gnomad NFE exome

AF:

0.588

Gnomad OTH exome

AF:

0.569

GnomAD4 exome

AF:

0.581

AC:

810568

AN:

1396214

Hom.:

236747

Cov.:

AF XY:

0.578

AC XY:

398444

AN XY:

688832

show subpopulations

African (AFR)

AF:

0.590

AC:

18638

AN:

31612

American (AMR)

AF:

0.685

AC:

24590

AN:

35884

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

15508

AN:

25146

East Asian (EAS)

AF:

0.490

AC:

17527

AN:

35738

South Asian (SAS)

AF:

0.496

AC:

39406

AN:

79428

European-Finnish (FIN)

AF:

0.602

AC:

27741

AN:

46046

Middle Eastern (MID)

AF:

0.424

AC:

2301

AN:

5422

European-Non Finnish (NFE)

AF:

0.586

AC:

632085

AN:

1079030

Other (OTH)

AF:

0.566

AC:

32772

AN:

57908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

23296

46591

69887

93182

116478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17560

35120

52680

70240

87800

<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:

0.589

AC:

89395

AN:

151878

Hom.:

26532

Cov.:

AF XY:

0.589

AC XY:

43686

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.593

AC:

24573

AN:

41466

American (AMR)

AF:

0.649

AC:

9923

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.620

AC:

2153

AN:

3470

East Asian (EAS)

AF:

0.447

AC:

2278

AN:

5092

South Asian (SAS)

AF:

0.495

AC:

2383

AN:

4810

European-Finnish (FIN)

AF:

0.594

AC:

6280

AN:

10578

Middle Eastern (MID)

AF:

0.469

AC:

137

AN:

292

European-Non Finnish (NFE)

AF:

0.590

AC:

40037

AN:

67868

Other (OTH)

AF:

0.554

AC:

1168

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1871

3741

5612

7482

9353

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

746

1492

2238

2984

3730

<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:

0.570

Hom.:

9497

Bravo

AF:

0.594

Asia WGS

AF:

0.471

AC:

1631

AN:

3454

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

-0.78

CADD

Benign

0.36

(source)

DANN

Benign

0.77

PhyloP100

-1.0

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