rs397517399

Variant names:

• chr18-31069003-GC-G
• rs397517399
• NM_024422.6:c.2398delG

Your query was ambiguous. Multiple possible variants found:

• chr18-31069003-GC-G
• chr18-31069003-GC-GCC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_024422.6(DSC2):​c.2398delG​(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 Uncertain_significance. Variant got 3 ACMG points.

• 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 rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2398delG	p.Ala800LeufsTer56	frameshift_variant	Exon 15 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2398delG	p.Ala800LeufsTer45	frameshift_variant	Exon 15 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1969delG	p.Ala657LeufsTer56	frameshift_variant	Exon 15 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1969delG	p.Ala657LeufsTer45	frameshift_variant	Exon 15 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2398delG	p.Ala800LeufsTer56	frameshift_variant	Exon 15 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2398delG	p.Ala800LeufsTer45	frameshift_variant	Exon 15 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1969delG	p.Ala657LeufsTer56	frameshift_variant	Exon 16 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1969delG	p.Ala657LeufsTer56	frameshift_variant	Exon 15 of 16			ENSP00000507826.1

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

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DSC2: PVS1:Strong, PM2 -

Apr 11, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); 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; This variant is associated with the following publications: (PMID: 32880476, 35819174, 31386562, 36971006, 28069705) -

Aug 31, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 17, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of DSC2-related conditions (PMID: 28069705, 32880476). ClinVar contains an entry for this variant (Variation ID: 46180). 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. -

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;