rs397517406

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_024422.6(DSC2):c.846C>G(p.Tyr282Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,072 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DSC2
NM_024422.6 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.27

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 Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-31086672-G-C is Pathogenic according to our data. Variant chr18-31086672-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46199.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSC2	NM_024422.6 linkuse as main transcript	c.846C>G	p.Tyr282Ter	stop_gained	7/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5 linkuse as main transcript	c.846C>G	p.Tyr282Ter	stop_gained	7/17		NP_004940.1
DSC2	NM_001406506.1 linkuse as main transcript	c.417C>G	p.Tyr139Ter	stop_gained	7/16		NP_001393435.1
DSC2	NM_001406507.1 linkuse as main transcript	c.417C>G	p.Tyr139Ter	stop_gained	7/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.846C>G	p.Tyr282Ter	stop_gained	7/16	1	NM_024422.6	ENSP00000280904	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.846C>G	p.Tyr282Ter	stop_gained	7/17	1		ENSP00000251081		Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.417C>G	p.Tyr139Ter	stop_gained	8/17			ENSP00000497441
DSC2	ENST00000682357.1 linkuse as main transcript	c.417C>G	p.Tyr139Ter	stop_gained	7/16			ENSP00000507826

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 46199). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr282*) in the DSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 04, 2021	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 13, 2019	The p.Tyr282X variant in DSC2 has been identified by our laboratory in 2 Caucasian siblings with ARVC and has also been reported in ClinVar (Variation ID 46199). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 282, which is predicted to lead to a truncated or absent protein. Truncating DSC2 variants have been reported in individuals with ARVC (http://arvcdatabase.info/) and DCM (Elliot 2010, Garcia-Pavia 2011), but overall their contribution to disease has not been well characterized. Therefore, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr282X variant is uncertain. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified via whole exome sequencing in one individual without a known diagnosis of ARVC in the published literature, but additional clinical information was not provided (PMID: 31638835); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 28471438, 31638835) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;A

Vest4

0.80

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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