Genetic Variant IRS2:p.Gly1263Val (chr13-109782266-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003749.3(IRS2):c.3788G>T(p.Gly1263Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000616 in 1,608,982 control chromosomes in the GnomAD database, including 5 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 (★★).

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

IRS2
NM_003749.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.07

Publications

4 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065819025).

BP6

Variant 13-109782266-C-A is Benign according to our data. Variant chr13-109782266-C-A is described in ClinVar as Benign. ClinVar VariationId is 785451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 498 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003749.3. 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
	IRS2	NM_003749.3	MANE Select	c.3788G>T	p.Gly1263Val	missense	Exon 1 of 2	NP_003740.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS2	ENST00000375856.5	TSL:1 MANE Select	c.3788G>T	p.Gly1263Val	missense	Exon 1 of 2	ENSP00000365016.3	Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.00328

AC:

497

AN:

151538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000961

GnomAD2 exomes

AF:

0.000780

AC:

181

AN:

232038

AF XY:

0.000614

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.000472

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000296

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000338

AC:

493

AN:

1457330

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

212

AN XY:

724892

show subpopulations

African (AFR)

AF:

0.0127

AC:

426

AN:

33416

American (AMR)

AF:

0.000606

AC:

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51198

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1110634

Other (OTH)

AF:

0.000482

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00328

AC:

498

AN:

151652

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

232

AN XY:

74110

show subpopulations

African (AFR)

AF:

0.0117

AC:

484

AN:

41356

American (AMR)

AF:

0.000720

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67810

Other (OTH)

AF:

0.000951

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000893

Hom.:

Bravo

AF:

0.00360

ESP6500AA

AF:

0.00944

AC:

ESP6500EA

AF:

0.000249

AC:

ExAC

AF:

0.000973

AC:

115

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.97

PhyloP100

1.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.0

REVEL

Benign

0.085

Sift

Benign

0.20

Sift4G

Benign

0.24

Polyphen

0.89

Vest4

0.24

MVP

0.75

ClinPred

0.0082

GERP RS

2.5

Varity_R

0.058

gMVP

0.28

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over