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rs12853546

chr13-109783567-G-Achr13-109783567-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_003749.3(IRS2):c.2487C>T(p.Pro829=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,549,162 control chromosomes in the GnomAD database, including 47,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.23 ( 4035 hom., cov: 34)
Exomes 𝑓: 0.25 ( 43363 hom. )

Consequence

IRS2
NM_003749.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.75
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 13-109783567-G-A is Benign according to our data. Variant chr13-109783567-G-A is described in ClinVar as [Benign]. Clinvar id is 3056733.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.74 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRS2NM_003749.3 linkuse as main transcriptc.2487C>T p.Pro829= synonymous_variant 1/2 ENST00000375856.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRS2ENST00000375856.5 linkuse as main transcriptc.2487C>T p.Pro829= synonymous_variant 1/21 NM_003749.3 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.228
AC:
34661
AN:
151992
Hom.:
4037
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.199
Gnomad AMI
AF:
0.313
Gnomad AMR
AF:
0.201
Gnomad ASJ
AF:
0.245
Gnomad EAS
AF:
0.222
Gnomad SAS
AF:
0.294
Gnomad FIN
AF:
0.242
Gnomad MID
AF:
0.404
Gnomad NFE
AF:
0.242
Gnomad OTH
AF:
0.258
GnomAD3 exomes
AF:
0.236
AC:
33798
AN:
143350
Hom.:
4221
AF XY:
0.242
AC XY:
18810
AN XY:
77582
show subpopulations
Gnomad AFR exome
AF:
0.198
Gnomad AMR exome
AF:
0.161
Gnomad ASJ exome
AF:
0.238
Gnomad EAS exome
AF:
0.217
Gnomad SAS exome
AF:
0.303
Gnomad FIN exome
AF:
0.239
Gnomad NFE exome
AF:
0.248
Gnomad OTH exome
AF:
0.257
GnomAD4 exome
AF:
0.246
AC:
344112
AN:
1397052
Hom.:
43363
Cov.:
77
AF XY:
0.248
AC XY:
170615
AN XY:
688968
show subpopulations
Gnomad4 AFR exome
AF:
0.202
Gnomad4 AMR exome
AF:
0.167
Gnomad4 ASJ exome
AF:
0.239
Gnomad4 EAS exome
AF:
0.188
Gnomad4 SAS exome
AF:
0.300
Gnomad4 FIN exome
AF:
0.236
Gnomad4 NFE exome
AF:
0.247
Gnomad4 OTH exome
AF:
0.259
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.228
AC:
34668
AN:
152110
Hom.:
4035
Cov.:
34
AF XY:
0.228
AC XY:
16917
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.199
Gnomad4 AMR
AF:
0.201
Gnomad4 ASJ
AF:
0.245
Gnomad4 EAS
AF:
0.222
Gnomad4 SAS
AF:
0.294
Gnomad4 FIN
AF:
0.242
Gnomad4 NFE
AF:
0.242
Gnomad4 OTH
AF:
0.259
Alfa
AF:
0.200
Hom.:
1012
Bravo
AF:
0.223
Asia WGS
AF:
0.250
AC:
868
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

IRS2-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 18, 2019This 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
-0.80
Cadd
Benign
2.6
Dann
Benign
0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12853546; hg19: chr13-110435914; COSMIC: COSV65477043; COSMIC: COSV65477043; API