NM_024422.6:c.2623C>T
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.Arg875*) 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
Consequence
NM_024422.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2623C>T | p.Arg875* | stop_gained | Exon 16 of 16 | ENST00000280904.11 | NP_077740.1 | |
DSC2 | NM_001406506.1 | c.2194C>T | p.Arg732* | stop_gained | Exon 16 of 16 | NP_001393435.1 | ||
DSC2 | NM_004949.5 | c.*125C>T | 3_prime_UTR_variant | Exon 17 of 17 | NP_004940.1 | |||
DSC2 | NM_001406507.1 | c.*125C>T | 3_prime_UTR_variant | Exon 17 of 17 | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2623C>T | p.Arg875* | stop_gained | Exon 16 of 16 | 1 | NM_024422.6 | ENSP00000280904.6 | ||
DSC2 | ENST00000251081 | c.*125C>T | 3_prime_UTR_variant | Exon 17 of 17 | 1 | ENSP00000251081.6 | ||||
DSC2 | ENST00000648081.1 | c.2194C>T | p.Arg732* | stop_gained | Exon 17 of 17 | ENSP00000497441.1 | ||||
DSC2 | ENST00000682357.1 | c.2194C>T | p.Arg732* | stop_gained | Exon 16 of 16 | ENSP00000507826.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151978Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251232Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135778
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727200
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151978Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74218
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:2
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. -
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not provided Uncertain:2
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). -
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not specified Uncertain:1
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
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Cardiomyopathy Uncertain:1
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
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. This variant has been reported in cardiomyopathy and exome cohorts (Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799; Chetruengchai W et al. J Hum Genet, 2022 Mar;67:137-142; Qafoud F et al. J Clin Med, 2024 Feb;13:). 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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at