chr18-31101938-C-T

Position:

chr18-31101938-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_024422.6(DSC2):c.34G>A(p.Gly12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,529,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0600

Variant links:

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

DSC2 links:

DSCAS (HGNC:):

DSCAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008911818).

BP6

Variant 18-31101938-C-T is Benign according to our data. Variant chr18-31101938-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 199777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31101938-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000848 (129/152176) while in subpopulation AFR AF= 0.00282 (117/41546). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6 linkuse as main transcript	c.34G>A	p.Gly12Arg	missense_variant	1/16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 linkuse as main transcript	c.34G>A	p.Gly12Arg	missense_variant	1/17		NP_004940.1	Q02487-2
DSCAS	NR_110785.1 linkuse as main transcript	n.136+215C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.34G>A	p.Gly12Arg	missense_variant	1/16	1	NM_024422.6	ENSP00000280904.6		Q02487-1

Frequencies

GnomAD3 genomes

AF:

0.000848

AC:

129

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000187

AC:

AN:

123006

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

67746

show subpopulations

Gnomad AFR exome

AF:

0.00299

Gnomad AMR exome

AF:

0.000216

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000141

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000263

GnomAD4 exome

AF:

0.000106

AC:

146

AN:

1377416

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

679588

show subpopulations

Gnomad4 AFR exome

AF:

0.00355

Gnomad4 AMR exome

AF:

0.000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000154

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000279

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.000848

AC:

129

AN:

152176

Hom.:

Cov.:

AF XY:

0.000928

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00282

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.00107

ExAC

AF:

0.000394

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 21, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 31, 2020

Variant summary: DSC2 c.34G>A (p.Gly12Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 123860 control chromosomes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.34G>A has been reported in the literature in individuals affected with Cardiovascular disease. These reports do not provide unequivocal conclusions about association of the variant with Cardiovascular disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Arrhythmogenic right ventricular dysplasia 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

DSC2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2020

This variant is associated with the following publications: (PMID: 21636032, 25351510) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial isolated arrhythmogenic right ventricular dysplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;.

Eigen

Benign

-0.067

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0089

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.29

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

1.0

D;D

Vest4

0.18

MutPred

0.62

Gain of MoRF binding (P = 0.0119);Gain of MoRF binding (P = 0.0119);

MVP

0.77

MPC

0.12

ClinPred

0.048

GERP RS

2.6

Varity_R

0.11

gMVP

0.53

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over