rs778636665
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_004415.4(DSP):āc.2546A>Gā(p.Tyr849Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 33)
Exomes š: 0.00018 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 5.10
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 Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.16195777).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2546A>G | p.Tyr849Cys | missense_variant | 18/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.2546A>G | p.Tyr849Cys | missense_variant | 18/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.2546A>G | p.Tyr849Cys | missense_variant | 18/24 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2546A>G | p.Tyr849Cys | missense_variant | 18/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.2546A>G | p.Tyr849Cys | missense_variant | 18/24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.2546A>G | p.Tyr849Cys | missense_variant | 18/24 | ENSP00000518230.1 | ||||
DSP | ENST00000684395.1 | n.1187A>G | non_coding_transcript_exon_variant | 5/5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251430Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135888
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GnomAD4 exome AF: 0.000182 AC: 266AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.000172 AC XY: 125AN XY: 727246
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
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 | Aug 24, 2015 | The p.Tyr849Cys variant in DSP has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 12/66738 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 778636665). Tyrosine (Tyr) at position 849 is not conserved in mammals or evolut ionarily distant species and 1 mammal (opossum) and several fish species carry a cysteine (Cys) at this position, raising the possibility that this change may b e tolerated. In summary, the clinical significance of the p.Tyr849Cys variant is uncertain. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | This missense variant replaces tyrosine with cysteine at codon 849 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 17/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 03, 2023 | This missense variant replaces tyrosine with cysteine at codon 849 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 17/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2016 | A variant of uncertain significance has been identified in the DSP gene. The Y849C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y849C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y849C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position that is conserved in mammals, C849 is wild type at this position in multiple non-mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2022 | The p.Y849C variant (also known as c.2546A>G), located in coding exon 18 of the DSP gene, results from an A to G substitution at nucleotide position 2546. The tyrosine at codon 849 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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