chr6-7582926-TGA-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004415.4(DSP):c.5673_5674del(p.Lys1892GlufsTer4) 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
DSP
NM_004415.4 frameshift
NM_004415.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.19
Genes affected
DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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. There are 96 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-7582926-TGA-T is Pathogenic according to our data. Variant chr6-7582926-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 464968.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.5673_5674del | p.Lys1892GlufsTer4 | frameshift_variant | 24/24 | ENST00000379802.8 | |
DSP | NM_001008844.3 | c.3876_3877del | p.Lys1293GlufsTer4 | frameshift_variant | 24/24 | ||
DSP | NM_001319034.2 | c.4344_4345del | p.Lys1449GlufsTer4 | frameshift_variant | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.5673_5674del | p.Lys1892GlufsTer4 | frameshift_variant | 24/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.3876_3877del | p.Lys1293GlufsTer4 | frameshift_variant | 24/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.4344_4345del | p.Lys1449GlufsTer4 | frameshift_variant | 24/24 | A2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 24, 2018 | This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the DSP gene (p.Lys1892Glufs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 978 amino acids of the DSP protein. This variant has not been reported in the literature in individuals with a DSP-related disease. A different truncation downstream of this variant (c.7901delG) has been determined to be pathogenic (PMID: 11063735). This suggests that deletion of this region of the DSP protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Splicing
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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