18-31068098-G-A

Position:

chr18-31068098-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_024422.6(DSC2):c.2623C>T(p.Arg875Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000136 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DSC2
NM_024422.6 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 3.74

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 Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0307 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSC2	NM_024422.6 linkuse as main transcript	c.2623C>T	p.Arg875Ter	stop_gained	16/16	ENST00000280904.11	NP_077740.1
DSC2	NM_001406506.1 linkuse as main transcript	c.2194C>T	p.Arg732Ter	stop_gained	16/16		NP_001393435.1
DSC2	NM_001406507.1 linkuse as main transcript	c.*125C>T		3_prime_UTR_variant	17/17		NP_001393436.1
DSC2	NM_004949.5 linkuse as main transcript	c.*125C>T		3_prime_UTR_variant	17/17		NP_004940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.2623C>T	p.Arg875Ter	stop_gained	16/16	1	NM_024422.6	ENSP00000280904	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.*125C>T		3_prime_UTR_variant	17/17	1		ENSP00000251081		Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.2194C>T	p.Arg732Ter	stop_gained	17/17			ENSP00000497441
DSC2	ENST00000682357.1 linkuse as main transcript	c.2194C>T	p.Arg732Ter	stop_gained	16/16			ENSP00000507826

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251232

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change creates a premature translational stop signal (p.Arg875*) in the DSC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the DSC2 protein. This variant is present in population databases (rs727504823, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179373). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2017	The R875X variant of uncertain significance in the DSC2 gene has not been published as pathogenic or been reported as benign to our knowledge. R875X, located in the last exon of the DSC2 gene, is predicted to cause loss of normal protein function via truncation of the final 27 amino acids of the protein product. This variant is not observed at a significant frequency in the Exome Aggregation Consortium (Lek et al., 2016). Other nonsense and frameshift variants in the DSC2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Gerull et al. (2013) identified a homozygous nonsense variant (Q554X) associated with ARVC in a Canadian Hutterite population. This nonsense variant lead to desmocollin-2 protein truncation, as determined by immunofluorescence imaging of endomyocardial biopsy specimens. The truncated protein was stable and localized at or near the intercalated discs. However, a different truncation variant that removes the C-terminal five amino acids (c.2686_2687dupGA) has been reported to be a polymorphism based on presence in controls (De Bortoli et al,. 2010). -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 24, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 08, 2013

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg875X var iant in DSC2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This nonsense variant leads to a premature term ination codon at position 875. This variant is located in the terminal exon, whe re nonsense mediated decay is unlikely, leading to a truncated protein lacking l ast 27 amino acids. One study reports a similar variant further upstream in the same exon that was shown to interfere with normal protein function (Asp859fsX4, Gehmlich 2011). On the other hand, a variant downstream (Ala897fs) is thought to be benign. In summary, is unclear whether this truncation will impact protein f unction and additional studies are required to fully establish its clinical sign ificance. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 25, 2014

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 08, 2023

This variant changes 1 nucleotide in exon 16 of the DSC2 gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282604 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2019

The p.R875* variant (also known as c.2623C>T), located in coding exon 16 of the DSC2 gene, results from a C to T substitution at nucleotide position 2623. This changes the amino acid from an arginine to a stop codon within coding exon 16. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of DSC2, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 27 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. -

Familial isolated arrhythmogenic right ventricular dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

D;N

Vest4

0.46

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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