chr6-7583113-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_004415.4(DSP):c.5851C>T(p.Arg1951*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,856 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
DSP
NM_004415.4 stop_gained
NM_004415.4 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 3.70
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 14 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 17 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-7583113-C-T is Pathogenic according to our data. Variant chr6-7583113-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7583113-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.5851C>T | p.Arg1951* | stop_gained | 24/24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.4522C>T | p.Arg1508* | stop_gained | 24/24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.4054C>T | p.Arg1352* | stop_gained | 24/24 | NP_001008844.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.5851C>T | p.Arg1951* | stop_gained | 24/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
| DSP | ENST00000418664.2 | c.4054C>T | p.Arg1352* | stop_gained | 24/24 | 1 | ENSP00000396591.2 | |||
| DSP | ENST00000710359.1 | c.4522C>T | p.Arg1508* | stop_gained | 24/24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727230
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32
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GnomAD4 genome
GnomAD4 genome
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32
EpiCase
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2023 | This variant changes 1 nucleotide in exon 24 of the DSP gene, creating a premature translation stop signal in the last exon. Although functional studies have not been reported, this variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disruption to the plakin repeat domains and downstream C-terminal sequence that have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). This variant has been reported in 6 unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 35474678, 36768812, Delpon 2016, Burns 2019, dissertation, The University of Sydney), in 1 individual affected with familial dilated cardiomyopathy (PMID: 26899768), hypertrophic cardiomyopathy (PMID: 26656175), and acute myocarditis (PMID: 34368507). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 25, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 222582). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 26899768). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1951*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 921 amino acid(s) of the DSP protein. - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 08, 2015 | - - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 22, 2023 | This variant changes 1 nucleotide in exon 24 of the DSP gene, creating a premature translation stop signal in the last exon. Although functional studies have not been reported, this variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disruption to the plakin repeat domains and downstream C-terminal sequence that have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). This variant has been reported in 6 unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 35474678, 36768812, Delpon 2016, Burns 2019, dissertation, The University of Sydney), in 1 individual affected with familial dilated cardiomyopathy (PMID: 26899768), hypertrophic cardiomyopathy (PMID: 26656175), and acute myocarditis (PMID: 34368507). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Arrhythmogenic cardiomyopathy Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University | Jan 10, 2023 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2022 | Nonsense variant predicted to result in protein truncation 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: 26656175, 32372669, 26899768, 31402444, Reza_2022_Cardiogenetics) - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 06, 2024 | The p.R1951* pathogenic mutation (also known as c.5851C>T), located in coding exon 24 of the DSP gene, results from a C to T substitution at nucleotide position 5851. This changes the amino acid from an arginine to a stop codon within coding exon 24. This alteration occurs at the 3' terminus of the DSP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 32% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace.2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation.2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This variant has been detected in individuals with features consistent with arrhythmogenic cardiomyopathy and dilated cardiomyopathy (Cuenca S et al. J Heart Lung Transplant, 2016 May;35:625-35; Chen V et al. Eur Heart J Case Rep, 2022 Mar;6:ytac105; Gasperetti A et al. JACC Adv, 2024 Mar;3:100832). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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