chr18-31079850-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024422.6(DSC2):c.1660C>T(p.Gln554Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,602 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024422.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.1660C>T | p.Gln554Ter | stop_gained | 11/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.1660C>T | p.Gln554Ter | stop_gained | 11/17 | ||
DSC2 | NM_001406506.1 | c.1231C>T | p.Gln411Ter | stop_gained | 11/16 | ||
DSC2 | NM_001406507.1 | c.1231C>T | p.Gln411Ter | stop_gained | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.1660C>T | p.Gln554Ter | stop_gained | 11/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.1660C>T | p.Gln554Ter | stop_gained | 11/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.1231C>T | p.Gln411Ter | stop_gained | 12/17 | ||||
DSC2 | ENST00000682357.1 | c.1231C>T | p.Gln411Ter | stop_gained | 11/16 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251114Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135706
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461602Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727102
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 235909). This premature translational stop signal has been observed in individual(s) with autosomal recessive and dominant DSC2-related conditions (PMID: 20152563, 23863954, 25497880). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln554*) in the DSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). - |
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, WITH OR WITHOUT MILD PALMOPLANTAR KERATODERMA Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | Nonsense variant in the C-terminus predicted to result in protein truncation and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Published functional studies demonstrate a damaging effect as this variant results in the production of a stable, partially-processed truncated protein, but the truncated protein product showed altered expression at the intercalated discs (Gerull et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23863954, 25497880, 27247959, 26310507, 26788539, 25921558, 27474350, 30454721, 34449993, 36142674, 35012021, 20152563, 31402444) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at