Genetic Variant IRS2:p.Pro1033Pro (chr13-109782955-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003749.3(IRS2):c.3099A>G(p.Pro1033Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,417,628 control chromosomes in the GnomAD database, including 45,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8318 hom., cov: 32)

Exomes 𝑓: 0.24 ( 37149 hom. )

Consequence

IRS2
NM_003749.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.13

Publications

12 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 13-109782955-T-C is Benign according to our data. Variant chr13-109782955-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 768633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.3099A>G	p.Pro1033Pro	synonymous_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.3099A>G	p.Pro1033Pro	synonymous_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

46764

AN:

150610

Hom.:

8299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.489

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.247

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.0627

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.276

Gnomad MID

AF:

0.195

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.265

GnomAD2 exomes

AF:

0.172

AC:

8620

AN:

50236

AF XY:

0.173

show subpopulations

Gnomad AFR exome

AF:

0.222

Gnomad AMR exome

AF:

0.0898

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.0207

Gnomad FIN exome

AF:

0.266

Gnomad NFE exome

AF:

0.186

Gnomad OTH exome

AF:

0.154

GnomAD4 exome

AF:

0.241

AC:

304951

AN:

1266904

Hom.:

37149

Cov.:

AF XY:

0.239

AC XY:

148452

AN XY:

620728

show subpopulations

African (AFR)

AF:

0.479

AC:

11282

AN:

23540

American (AMR)

AF:

0.164

AC:

2600

AN:

15876

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

3519

AN:

18766

East Asian (EAS)

AF:

0.0756

AC:

2274

AN:

30078

South Asian (SAS)

AF:

0.174

AC:

10222

AN:

58706

European-Finnish (FIN)

AF:

0.268

AC:

11428

AN:

42624

Middle Eastern (MID)

AF:

0.157

AC:

741

AN:

4722

European-Non Finnish (NFE)

AF:

0.246

AC:

250983

AN:

1021112

Other (OTH)

AF:

0.231

AC:

11902

AN:

51480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

10575

21150

31725

42300

52875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9184

18368

27552

36736

45920

<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:

0.311

AC:

46833

AN:

150724

Hom.:

8318

Cov.:

AF XY:

0.308

AC XY:

22640

AN XY:

73612

show subpopulations

African (AFR)

AF:

0.489

AC:

20164

AN:

41236

American (AMR)

AF:

0.247

AC:

3750

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

800

AN:

3466

East Asian (EAS)

AF:

0.0627

AC:

317

AN:

5054

South Asian (SAS)

AF:

0.191

AC:

887

AN:

4632

European-Finnish (FIN)

AF:

0.276

AC:

2849

AN:

10308

Middle Eastern (MID)

AF:

0.201

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.255

AC:

17249

AN:

67558

Other (OTH)

AF:

0.263

AC:

550

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1525

3051

4576

6102

7627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.293

Hom.:

715

Bravo

AF:

0.314

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

IRS2-related disorder

Benign:1

Oct 28, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.27

(source)

DANN

Benign

0.27

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over