rs794728136
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000379802.8(DSP):c.273del(p.Glu92AsnfsTer2) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
DSP
ENST00000379802.8 frameshift, splice_region
ENST00000379802.8 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.90
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 18 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 6-7555819-CT-C is Pathogenic according to our data. Variant chr6-7555819-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.273del | p.Glu92AsnfsTer2 | frameshift_variant, splice_region_variant | 2/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.273del | p.Glu92AsnfsTer2 | frameshift_variant, splice_region_variant | 2/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.273del | p.Glu92AsnfsTer2 | frameshift_variant, splice_region_variant | 2/24 | NP_001008844.1 | ||
DSP | NM_001406591.1 | c.273del | p.Glu92AsnfsTer2 | frameshift_variant, splice_region_variant | 2/11 | NP_001393520.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.273del | p.Glu92AsnfsTer2 | frameshift_variant, splice_region_variant | 2/24 | 1 | NM_004415.4 | ENSP00000369129 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 20, 2016 | The p.Glu92fs variant in DSP has not been previously reported in individuals wit h cardiomyopathy, and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 92 and leads to a premature termination codon 2 amino acid s downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DSP gene is an established diseas e mechanism in individuals with ARVC and/or DCM. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu92f s variant is likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2014 | Although the c.273delT mutation in the DSP gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Glutamic acid 92, changing it to an Asparagine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Glu92AsnfsX2. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the DSP gene have been reported in association with cardiomyopathy. In summary, c.273delT in the DSP gene is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at