rs397516927
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004415.4(DSP):c.2848del(p.Ile950LeufsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
DSP
NM_004415.4 frameshift
NM_004415.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.70
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-7577007-CA-C is Pathogenic according to our data. Variant chr6-7577007-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 855123.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-7577007-CA-C is described in Lovd as [Likely_pathogenic]. Variant chr6-7577007-CA-C is described in Lovd as [Pathogenic]. Variant chr6-7577007-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2848del | p.Ile950LeufsTer27 | frameshift_variant | 20/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.2848del | p.Ile950LeufsTer27 | frameshift_variant | 20/24 | ||
DSP | NM_001008844.3 | c.2848del | p.Ile950LeufsTer27 | frameshift_variant | 20/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2848del | p.Ile950LeufsTer27 | frameshift_variant | 20/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.2848del | p.Ile950LeufsTer27 | frameshift_variant | 20/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.2848del | p.Ile950LeufsTer27 | frameshift_variant | 20/24 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459802Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726010
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1459802
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30
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0
AN XY:
726010
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
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 | Dec 06, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 25157032). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile950Leufs*27) in the DSP gene. It is expected to result in an absent or disrupted protein product. - |
Arrhythmogenic cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University | Jan 10, 2023 | - - |
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