chr13-109782955-T-C

Variant names:

• chr13-109782955-T-C
• rs9583424
• NM_003749.3:c.3099A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13

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]

ACMG classification

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 id 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	c.3099A>G	p.Pro1033Pro	synonymous_variant	Exon 1 of 2	ENST00000375856.5	NP_003740.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS2	ENST00000375856.5	c.3099A>G	p.Pro1033Pro	synonymous_variant	Exon 1 of 2	1	NM_003749.3	ENSP00000365016.3

Frequencies

GnomAD3 genomes AF: 0.310 AC: 46764 AN: 150610 Hom.: 8299 Cov.: 32

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

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.: 50 AF XY: 0.239 AC XY: 148452 AN XY: 620728

Gnomad4 AFR exome AF: 0.479 AC: 11282 AN: 23540

Gnomad4 AMR exome AF: 0.164 AC: 2600 AN: 15876

Gnomad4 ASJ exome AF: 0.188 AC: 3519 AN: 18766

Gnomad4 EAS exome AF: 0.0756 AC: 2274 AN: 30078

Gnomad4 SAS exome AF: 0.174 AC: 10222 AN: 58706

Gnomad4 FIN exome AF: 0.268 AC: 11428 AN: 42624

Gnomad4 NFE exome AF: 0.246 AC: 250983 AN: 1021112

Gnomad4 Remaining exome AF: 0.231 AC: 11902 AN: 51480

GnomAD4 genome AF: 0.311 AC: 46833 AN: 150724 Hom.: 8318 Cov.: 32 AF XY: 0.308 AC XY: 22640 AN XY: 73612

Gnomad4 AFR AF: 0.489 AC: 0.48899 AN: 0.48899

Gnomad4 AMR AF: 0.247 AC: 0.247003 AN: 0.247003

Gnomad4 ASJ AF: 0.231 AC: 0.230814 AN: 0.230814

Gnomad4 EAS AF: 0.0627 AC: 0.0627226 AN: 0.0627226

Gnomad4 SAS AF: 0.191 AC: 0.191494 AN: 0.191494

Gnomad4 FIN AF: 0.276 AC: 0.276387 AN: 0.276387

Gnomad4 NFE AF: 0.255 AC: 0.255321 AN: 0.255321

Gnomad4 OTH AF: 0.263 AC: 0.263158 AN: 0.263158

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

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DANN	Benign	0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9583424; hg19: chr13-110435302; COSMIC: COSV65478240; COSMIC: COSV65478240;