Genetic Variant NM_003749.3:c.4012+79C>T (chr13-109781963-G-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.4012+79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,508,380 control chromosomes in the GnomAD database, including 25,490 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 0.22 ( 4408 hom., cov: 33)

Exomes 𝑓: 0.17 ( 21082 hom. )

Consequence

IRS2
NM_003749.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.875

Publications

10 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=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.4012+79C>T		intron_variant	Intron 1 of 1	ENST00000375856.5	NP_003740.2	Q9Y4H2Q9P084

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS2	ENST00000375856.5 link	c.4012+79C>T		intron_variant	Intron 1 of 1	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33355

AN:

152026

Hom.:

4401

Cov.:

show subpopulations

Gnomad AFR

AF:

0.369

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.165

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.0207

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.180

GnomAD4 exome

AF:

0.170

AC:

230565

AN:

1356236

Hom.:

21082

AF XY:

0.170

AC XY:

114490

AN XY:

673144

show subpopulations

African (AFR)

AF:

0.380

AC:

12055

AN:

31748

American (AMR)

AF:

0.133

AC:

4922

AN:

37024

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

4236

AN:

24880

East Asian (EAS)

AF:

0.0385

AC:

1463

AN:

37998

South Asian (SAS)

AF:

0.158

AC:

12642

AN:

80198

European-Finnish (FIN)

AF:

0.166

AC:

7418

AN:

44716

Middle Eastern (MID)

AF:

0.113

AC:

610

AN:

5408

European-Non Finnish (NFE)

AF:

0.171

AC:

177783

AN:

1037424

Other (OTH)

AF:

0.166

AC:

9436

AN:

56840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

9918

19836

29755

39673

49591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6274

12548

18822

25096

31370

<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:

0.219

AC:

33390

AN:

152144

Hom.:

4408

Cov.:

AF XY:

0.215

AC XY:

15981

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.369

AC:

15305

AN:

41476

American (AMR)

AF:

0.165

AC:

2523

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

670

AN:

3472

East Asian (EAS)

AF:

0.0206

AC:

106

AN:

5156

South Asian (SAS)

AF:

0.149

AC:

718

AN:

4828

European-Finnish (FIN)

AF:

0.166

AC:

1760

AN:

10602

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.173

AC:

11780

AN:

67982

Other (OTH)

AF:

0.179

AC:

379

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1271

2543

3814

5086

6357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.184

Hom.:

3620

Bravo

AF:

0.225

Asia WGS

AF:

0.103

AC:

360

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.56

(source)

DANN

Benign

0.49

PhyloP100

-0.88

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