Genetic Variant IRS2:p.Gly1057Asp (chr13-109782884-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_003749.3(IRS2):c.3170G>A(p.Gly1057Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,562,240 control chromosomes in the GnomAD database, including 86,943 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,risk factor (no stars).

Frequency

Genomes: 𝑓 0.29 ( 7081 hom., cov: 32)

Exomes 𝑓: 0.33 ( 79862 hom. )

Consequence

IRS2
NM_003749.3 missense

Scores

Clinical Significance

Benign; risk factor no assertion criteria provided B:1O:1

Conservation

PhyloP100: 0.425

Publications

149 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.8087368E-4).

BP6

Variant 13-109782884-C-T is Benign according to our data. Variant chr13-109782884-C-T is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 8820.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.3170G>A	p.Gly1057Asp	missense_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.3170G>A	p.Gly1057Asp	missense_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.287

AC:

43522

AN:

151442

Hom.:

7078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.386

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.296

Gnomad NFE

AF:

0.341

Gnomad OTH

AF:

0.295

GnomAD2 exomes

AF:

0.350

AC:

54931

AN:

156960

AF XY:

0.345

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.471

Gnomad ASJ exome

AF:

0.404

Gnomad EAS exome

AF:

0.401

Gnomad FIN exome

AF:

0.340

Gnomad NFE exome

AF:

0.341

Gnomad OTH exome

AF:

0.350

GnomAD4 exome

AF:

0.332

AC:

469031

AN:

1410682

Hom.:

79862

Cov.:

AF XY:

0.331

AC XY:

230790

AN XY:

696988

show subpopulations

African (AFR)

AF:

0.118

AC:

3819

AN:

32470

American (AMR)

AF:

0.460

AC:

16856

AN:

36668

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

10263

AN:

25204

East Asian (EAS)

AF:

0.408

AC:

15209

AN:

37268

South Asian (SAS)

AF:

0.282

AC:

22692

AN:

80504

European-Finnish (FIN)

AF:

0.338

AC:

16316

AN:

48296

Middle Eastern (MID)

AF:

0.260

AC:

1473

AN:

5668

European-Non Finnish (NFE)

AF:

0.335

AC:

363437

AN:

1086150

Other (OTH)

AF:

0.324

AC:

18966

AN:

58454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

18734

37468

56201

74935

93669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11748

23496

35244

46992

58740

<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:

0.287

AC:

43535

AN:

151558

Hom.:

7081

Cov.:

AF XY:

0.291

AC XY:

21534

AN XY:

74054

show subpopulations

African (AFR)

AF:

0.125

AC:

5165

AN:

41414

American (AMR)

AF:

0.404

AC:

6172

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

1354

AN:

3468

East Asian (EAS)

AF:

0.385

AC:

1944

AN:

5050

South Asian (SAS)

AF:

0.289

AC:

1393

AN:

4818

European-Finnish (FIN)

AF:

0.331

AC:

3473

AN:

10480

Middle Eastern (MID)

AF:

0.281

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.341

AC:

23078

AN:

67748

Other (OTH)

AF:

0.294

AC:

620

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1513

3026

4539

6052

7565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

440

880

1320

1760

2200

<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:

0.327

Hom.:

8226

Bravo

AF:

0.287

TwinsUK

AF:

0.331

AC:

1228

ALSPAC

AF:

0.335

AC:

1292

ESP6500AA

AF:

0.117

AC:

464

ESP6500EA

AF:

0.290

AC:

2312

ExAC

AF:

0.264

AC:

27791

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1Other: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). -

Type 2 diabetes mellitus

Other:1

Oct 01, 2001

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.30

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.82

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.47

MetaRNN

Benign

0.00038

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

PhyloP100

0.42

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.57

REVEL

Benign

0.052

Sift

Benign

0.22

Sift4G

Benign

0.33

Polyphen

0.089

Vest4

0.048

ClinPred

0.0068

GERP RS

2.1

Varity_R

0.033

gMVP

0.37

Mutation Taster

=98/2

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