dbSNP rs1865434: IRS2:c.*43G>A (chr13-109756261-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003749.3(IRS2):c.*43G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 1,546,828 control chromosomes in the GnomAD database, including 554,526 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.

Frequency

Genomes: 𝑓 0.84 ( 54076 hom., cov: 31)

Exomes 𝑓: 0.85 ( 500450 hom. )

Consequence

IRS2
NM_003749.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.134

Publications

26 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 -12 ACMG points.

BP4

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

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.*43G>A		3_prime_UTR_variant	Exon 2 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.*43G>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.843

AC:

128117

AN:

152012

Hom.:

54050

Cov.:

show subpopulations

Gnomad AFR

AF:

0.813

Gnomad AMI

AF:

0.850

Gnomad AMR

AF:

0.882

Gnomad ASJ

AF:

0.887

Gnomad EAS

AF:

0.778

Gnomad SAS

AF:

0.828

Gnomad FIN

AF:

0.859

Gnomad MID

AF:

0.892

Gnomad NFE

AF:

0.852

Gnomad OTH

AF:

0.858

GnomAD2 exomes

AF:

0.855

AC:

214608

AN:

251068

AF XY:

0.853

show subpopulations

Gnomad AFR exome

AF:

0.806

Gnomad AMR exome

AF:

0.919

Gnomad ASJ exome

AF:

0.883

Gnomad EAS exome

AF:

0.784

Gnomad FIN exome

AF:

0.865

Gnomad NFE exome

AF:

0.855

Gnomad OTH exome

AF:

0.861

GnomAD4 exome

AF:

0.847

AC:

1180696

AN:

1394698

Hom.:

500450

Cov.:

AF XY:

0.846

AC XY:

590729

AN XY:

698004

show subpopulations

African (AFR)

AF:

0.808

AC:

25945

AN:

32102

American (AMR)

AF:

0.914

AC:

40813

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.883

AC:

22732

AN:

25740

East Asian (EAS)

AF:

0.784

AC:

30842

AN:

39342

South Asian (SAS)

AF:

0.832

AC:

70649

AN:

84924

European-Finnish (FIN)

AF:

0.861

AC:

45932

AN:

53364

Middle Eastern (MID)

AF:

0.860

AC:

4840

AN:

5626

European-Non Finnish (NFE)

AF:

0.847

AC:

889560

AN:

1050736

Other (OTH)

AF:

0.848

AC:

49383

AN:

58228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

8112

16224

24336

32448

40560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19540

39080

58620

78160

97700

<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:

0.843

AC:

128192

AN:

152130

Hom.:

54076

Cov.:

AF XY:

0.843

AC XY:

62689

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.813

AC:

33716

AN:

41496

American (AMR)

AF:

0.883

AC:

13503

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.887

AC:

3080

AN:

3472

East Asian (EAS)

AF:

0.777

AC:

3994

AN:

5138

South Asian (SAS)

AF:

0.828

AC:

3988

AN:

4818

European-Finnish (FIN)

AF:

0.859

AC:

9107

AN:

10596

Middle Eastern (MID)

AF:

0.888

AC:

261

AN:

294

European-Non Finnish (NFE)

AF:

0.852

AC:

57964

AN:

67996

Other (OTH)

AF:

0.856

AC:

1804

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1046

2093

3139

4186

5232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.856

Hom.:

71441

Bravo

AF:

0.843

Asia WGS

AF:

0.811

AC:

2824

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.1

(source)

DANN

Benign

0.39

PhyloP100

0.13

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

Computational scores

Splicing

Publications

Other links and lift over