rs397517399

chr18-31069003-GC-Gchr18-31069003-GC-GCC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_024422.6(DSC2):c.2398del(p.Ala800LeufsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DSC2 NM_024422.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 0.00800

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31069003-GC-G is Pathogenic according to our data. Variant chr18-31069003-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46180.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}. Variant chr18-31069003-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.2398del	p.Ala800LeufsTer56	frameshift_variant	15/16	ENST00000280904.11
DSC2	NM_004949.5	c.2398del	p.Ala800LeufsTer45	frameshift_variant	15/17
DSC2	NM_001406506.1	c.1969del	p.Ala657LeufsTer56	frameshift_variant	15/16
DSC2	NM_001406507.1	c.1969del	p.Ala657LeufsTer45	frameshift_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.2398del	p.Ala800LeufsTer56	frameshift_variant	15/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.2398del	p.Ala800LeufsTer45	frameshift_variant	15/17	1
DSC2	ENST00000648081.1	c.1969del	p.Ala657LeufsTer56	frameshift_variant	16/17
DSC2	ENST00000682357.1	c.1969del	p.Ala657LeufsTer56	frameshift_variant	15/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2023	Frameshift variant predicted to result in abnormal protein length as the last 102 amino acids are replaced with 55 different amino acids, and other similar variants have been reported in HGMD; Reported in conjunction with a pathogenic PKP2 variant in an individual with arrhythmogenic cardiomyopathy (PMID: 28069705); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32880476, 35819174, 31386562, 28069705) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	DSC2: PVS1:Strong, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 31, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 17, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The 2398delG va riant (DSC2) has not been reported in the literature but has been identified in 1 individual with ARVD/C (this individual) tested by our laboratory. This frames hift variant is predicted to alter the protein?s amino acid sequence beginning a t position 800 and lead to a premature termination codon 56 amino acids downstre am. Premature termination often leads to degradation of the mRNA and therefore reduced or absent protein; however, this typically does not happen when the prem ature stop codon is located in the last exon as is the case in this individual. In summary, the presence of a variant in the DSC2 gene is consistent with this i ndividual?s clinical diagnosis. However, there is not yet enough data on whethe r this type of variant would cause ARVC. It is more likely that this variant ca uses disease but additional information is needed to establish this with confide nce. -

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2022

This sequence change creates a premature translational stop signal (p.Ala800Leufs*56) in the DSC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 102 amino acid(s) of the DSC2 protein. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 46180). This premature translational stop signal has been observed in individual(s) with clinical features of DSC2-related conditions (PMID: 28069705, 32880476). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

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: rs397517399; hg19: chr18-28648969;