rs200056085

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_024422.6(DSC2):c.2687_2688insGA(p.Ala897LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0106 in 1,613,982 control chromosomes in the GnomAD database, including 114 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 103 hom. )

Consequence

DSC2
NM_024422.6 frameshift

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:21

Conservation

PhyloP100: 5.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM4

Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 903 codons.

BP6

Variant 18-31068033-T-TTC is Benign according to our data. Variant chr18-31068033-T-TTC is described in ClinVar as [Likely_benign]. Clinvar id is 46186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00872 (1327/152258) while in subpopulation NFE AF= 0.0146 (991/68012). AF 95% confidence interval is 0.0138. There are 11 homozygotes in gnomad4. There are 633 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.2687_2688insGA	p.Ala897LysfsTer4	frameshift_variant	16/16	ENST00000280904.11
DSC2	NM_001406506.1 linkuse as main transcript	c.2258_2259insGA	p.Ala754LysfsTer4	frameshift_variant	16/16
DSC2	NM_001406507.1 linkuse as main transcript	c.189_190insGA		3_prime_UTR_variant	17/17
DSC2	NM_004949.5 linkuse as main transcript	c.189_190insGA		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.2687_2688insGA	p.Ala897LysfsTer4	frameshift_variant	16/16	1	NM_024422.6	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.189_190insGA		3_prime_UTR_variant	17/17	1			Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.2258_2259insGA	p.Ala754LysfsTer4	frameshift_variant	17/17
DSC2	ENST00000682357.1 linkuse as main transcript	c.2258_2259insGA	p.Ala754LysfsTer4	frameshift_variant	16/16

Frequencies

GnomAD3 genomes

AF:

0.00872

AC:

1327

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00623

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00915

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00843

AC:

2119

AN:

251230

Hom.:

AF XY:

0.00854

AC XY:

1159

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00297

Gnomad FIN exome

AF:

0.00915

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.0108

AC:

15742

AN:

1461724

Hom.:

103

Cov.:

AF XY:

0.0106

AC XY:

7673

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00548

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00340

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.0126

Gnomad4 OTH exome

AF:

0.00907

GnomAD4 genome

AF:

0.00872

AC:

1327

AN:

152258

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00622

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00915

Gnomad4 NFE

AF:

0.0146

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.00808

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 14, 2013	Ala897fs in exon 16 of DSC2: This variant is not expected to have clinical signi ficance because it has been identified in 1.3% (111/8254) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/). This variant leads to a frameshift starting at pos ition 897 and a subsequent truncation that removes the terminal amino acid of th e DSC2 protein. Although it was initially reported in 3 Caucasian individuals wi th ARVC probands while absent from 400 ethnically matched control alleles, it ha s subsequently been detected in several control cohorts at frequencies that argu e against a disease causing role (0.8%-1.5%, see http://arvcdatabase.info). The overall frequency of this variant strongly argues against a primary disease-caus ing role, although we cannot rule out that it may modify disease severity when p resent with other disease-causing variants. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DSC2: BS1, BS2 -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 24, 2017	- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 01, 2015

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 08, 2013

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2013

No disease association in appropriately sized case-control study(ies) -

Familial isolated arrhythmogenic right ventricular dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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