Genetic Variant IRS2:c.*836G>T (chr13-109755468-C-A) – 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.*836G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 217,118 control chromosomes in the GnomAD database, including 10,240 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 0.27 ( 6484 hom., cov: 32)

Exomes 𝑓: 0.33 ( 3756 hom. )

Consequence

IRS2
NM_003749.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.499

Publications

13 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:

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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=-0.72).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.*836G>T		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.*836G>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.271

AC:

41208

AN:

151832

Hom.:

6484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.271

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.263

Gnomad MID

AF:

0.274

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.269

GnomAD4 exome

AF:

0.332

AC:

21663

AN:

65168

Hom.:

3756

Cov.:

AF XY:

0.330

AC XY:

9953

AN XY:

30172

show subpopulations

African (AFR)

AF:

0.121

AC:

363

AN:

3006

American (AMR)

AF:

0.407

AC:

779

AN:

1914

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1378

AN:

4162

East Asian (EAS)

AF:

0.457

AC:

4351

AN:

9524

South Asian (SAS)

AF:

0.330

AC:

189

AN:

572

European-Finnish (FIN)

AF:

0.205

AC:

AN:

Middle Eastern (MID)

AF:

0.286

AC:

115

AN:

402

European-Non Finnish (NFE)

AF:

0.318

AC:

12748

AN:

40028

Other (OTH)

AF:

0.314

AC:

1731

AN:

5516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

687

1374

2062

2749

3436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.271

AC:

41221

AN:

151950

Hom.:

6484

Cov.:

AF XY:

0.274

AC XY:

20333

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.114

AC:

4744

AN:

41456

American (AMR)

AF:

0.385

AC:

5879

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

1127

AN:

3470

East Asian (EAS)

AF:

0.458

AC:

2355

AN:

5146

South Asian (SAS)

AF:

0.303

AC:

1458

AN:

4816

European-Finnish (FIN)

AF:

0.263

AC:

2774

AN:

10532

Middle Eastern (MID)

AF:

0.253

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.324

AC:

21996

AN:

67946

Other (OTH)

AF:

0.268

AC:

567

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1455

2910

4365

5820

7275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.304

Hom.:

5980

Bravo

AF:

0.275

Asia WGS

AF:

0.342

AC:

1191

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.7

(source)

DANN

Benign

0.79

PhyloP100

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

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

Computational scores

Splicing

Publications

Other links and lift over