Genetic Variant NM_003749.3:c.3146C>A (chr13-109782908-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003749.3(IRS2):c.3146C>A(p.Ala1049Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,395,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1049V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

IRS2
NM_003749.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.151

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08594003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS2	NM_003749.3 link	c.3146C>A	p.Ala1049Asp	missense_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.3146C>A	p.Ala1049Asp	missense_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3		Q9Y4H2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1395932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688814

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31268

American (AMR)

AF:

0.00

AC:

AN:

35668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24940

East Asian (EAS)

AF:

0.00

AC:

AN:

35908

South Asian (SAS)

AF:

0.00

AC:

AN:

79304

European-Finnish (FIN)

AF:

0.0000210

AC:

AN:

47606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077846

Other (OTH)

AF:

0.00

AC:

AN:

57818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.4

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.31

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.39

M_CAP

Benign

0.027

MetaRNN

Benign

0.086

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

-0.15

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.22

REVEL

Benign

0.020

Sift

Benign

0.10

Sift4G

Benign

0.59

Polyphen

0.12

Vest4

0.079

MutPred

0.20

Loss of sheet (P = 0.0181);

MVP

0.23

ClinPred

0.080

GERP RS

0.12

Varity_R

0.078

gMVP

0.23

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over