rs727504823
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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
NM_024422.6 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.74
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]
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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 | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSC2 | NM_024422.6 | c.2623C>T | p.Arg875Ter | stop_gained | 16/16 | ENST00000280904.11 | NP_077740.1 | |
| DSC2 | NM_001406506.1 | c.2194C>T | p.Arg732Ter | stop_gained | 16/16 | NP_001393435.1 | ||
| DSC2 | NM_001406507.1 | c.*125C>T | 3_prime_UTR_variant | 17/17 | NP_001393436.1 | |||
| DSC2 | NM_004949.5 | 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 | c.2623C>T | p.Arg875Ter | stop_gained | 16/16 | 1 | NM_024422.6 | ENSP00000280904 | P1 | |
| DSC2 | ENST00000251081.8 | c.*125C>T | 3_prime_UTR_variant | 17/17 | 1 | ENSP00000251081 | ||||
| DSC2 | ENST00000648081.1 | c.2194C>T | p.Arg732Ter | stop_gained | 17/17 | ENSP00000497441 | ||||
| DSC2 | ENST00000682357.1 | c.2194C>T | p.Arg732Ter | stop_gained | 16/16 | ENSP00000507826 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 151978Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251232Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135778
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727200
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GnomAD4 genome 0.0000132 AC: 2AN: 151978Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74218
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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 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;N
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at