rs876657798
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_004415.4(DSP):c.6610C>T(p.Gln2204Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).
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
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.13
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 10 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 56 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.6610C>T | p.Gln2204Ter | stop_gained | 24/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.5281C>T | p.Gln1761Ter | stop_gained | 24/24 | ||
DSP | NM_001008844.3 | c.4813C>T | p.Gln1605Ter | stop_gained | 24/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.6610C>T | p.Gln2204Ter | stop_gained | 24/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.4813C>T | p.Gln1605Ter | stop_gained | 24/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.5281C>T | p.Gln1761Ter | stop_gained | 24/24 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727230
GnomAD4 exome
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2
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1461856
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32
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2
AN XY:
727230
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 02, 2015 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln2204X variant in DSP has not been previously reported in individuals with cardiomyopat hy and was absent from large population studies. This nonsense variant leads to a premature termination codon within the last exon. Nonsense variants are well r eported patients with ARVC (http://arvcdatabase.info/) and this type of variant is generally expected to lead to nonsense medicated mRNA decay (NMD), resulting in loss of function. However, this is less likely in the last exon and therefore the effect of this variant on the protein is not clear. Some evidence for a rol e in ARVC comes from reports of homozygous truncating variants in the last exon in individuals with Carvajal syndrome and/or acantholytic epidermolysis bullosa (Cheong 2005, Jonkman 2005, Rasmussen 2013), though it is less clear if heterozy gous carriers exhibit any features. In summary, while there is some suspicion f or a pathogenic role, the clinical significance of the p.Gln2204X variant is unc ertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
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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