rs397517390
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_024422.6(DSC2):c.1234_1235insA(p.Thr412AsnfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
DSC2
NM_024422.6 frameshift
NM_024422.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.51
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 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 18-31082266-G-GT is Pathogenic according to our data. Variant chr18-31082266-G-GT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46164.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.1234_1235insA | p.Thr412AsnfsTer3 | frameshift_variant | 9/16 | ENST00000280904.11 | |
DSC2 | NM_001406506.1 | c.805_806insA | p.Thr269AsnfsTer3 | frameshift_variant | 9/16 | ||
DSC2 | NM_001406507.1 | c.805_806insA | p.Thr269AsnfsTer3 | frameshift_variant | 9/17 | ||
DSC2 | NM_004949.5 | c.1234_1235insA | p.Thr412AsnfsTer3 | frameshift_variant | 9/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.1234_1235insA | p.Thr412AsnfsTer3 | frameshift_variant | 9/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.1234_1235insA | p.Thr412AsnfsTer3 | frameshift_variant | 9/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.805_806insA | p.Thr269AsnfsTer3 | frameshift_variant | 10/17 | ||||
DSC2 | ENST00000682357.1 | c.805_806insA | p.Thr269AsnfsTer3 | frameshift_variant | 9/16 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2023 | Identified in two siblings with ARVC, however, diagnostic criteria is unclear and functional studies were not performed (PMID: 22458570); Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 22458570) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 13, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Thr412fs va riant in DSC2 has been reported in 1 individual with ARVC and 1 affected relativ e (Rajkumar 2012), and was not identified in large population studies. This vari ant has now been identified by our laboratory in 2 individuals with ARVC from on e family (this individual's sons). These individuals carried a second, possibly disease-causing variant, which was also detected in isolation in an affected rel ative. This frameshift variant is predicted to alter the protein?s amino acid se quence beginning at position 412 and lead to a premature termination codon 3 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants in DSC2 are known to be involved in t he etiology of ARVC. Although this data supports that the Thr412fs variant may b e pathogenic, additional studies are needed to fully assess its clinical signifi cance. - |
Computational scores
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Calibrated prediction
Score
Prediction
Splicing
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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