rs121912998
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_004415.4(DSP):c.88G>A(p.Val30Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,595,514 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V30A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.88G>A | p.Val30Met | missense_variant | 1/24 | ENST00000379802.8 | |
DSP-AS1 | NR_183331.1 | n.39-950C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.88G>A | p.Val30Met | missense_variant | 1/24 | 1 | NM_004415.4 | P2 | |
DSP-AS1 | ENST00000690863.2 | n.344+768C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00116 AC: 176AN: 152210Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00159 AC: 331AN: 208172Hom.: 3 AF XY: 0.00190 AC XY: 216AN XY: 113510
GnomAD4 exome AF: 0.00136 AC: 1956AN: 1443186Hom.: 4 Cov.: 32 AF XY: 0.00155 AC XY: 1110AN XY: 716308
GnomAD4 genome ? AF: 0.00115 AC: 175AN: 152328Hom.: 1 Cov.: 33 AF XY: 0.00138 AC XY: 103AN XY: 74494
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2020 | This variant is associated with the following publications: (PMID: 32268277, 31028938, 25637381, 16917092, 20152563, 21636032, 23137101, 23671136, 24070718, 20129281, 23861362, 26656175, 27153395, 26332594, 26569459, 23299917, 28473349, 25985138, 27435932, 28798025, 31019283, 31402444, 33232181) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 24, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | DSP: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:1Benign:5
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Feb 06, 2014 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we consider this a variant of uncertain significance. This variant has been identified in multiple probands with ARVC and in one SCICD center patient with conduction system disease, biventricular dysfunction and a history of SCD. Yang et al (2006) first reported the variant in an individual with ARVC in a publication that only reports on DSP variants. In all other published cases this variant occurs with additional variants. Bauce et al (2010) identified an individual with ARVC and two DSP variants, p.Val30Met and p.Arg2541Lys. Each variant was detected in isolation in separate affected family members. Xu et al (2010) report a proband with the p.Val30Met variant as well as a nonsense and a missense variant in the PKP2 gene. This is a conservative amino acid change with the replacement on a nonpolar Valine with a nonpolar Methionine. Valine is not conserved across species and several species harbor a Methionine at this codon. In vitro studies reported by Yang et al (2006) showed that when this variant is present desmoplakin is trapped in the cytoplasm and fails to localize to the cell membrane. In total the variant has been seen in 21 of 9109 published controls and publicly available general population samples (as of 12/6/14). Across available publications the variant is absent in 1150 presumably healthy control individuals. However, more recently Kapplinger et al (2011) reported the variant in 1 of 427 presumably healthy individuals and the variant is reported in 16 of 4,269 European individuals in the NHLBI Exome Sequencing Project dataset and 0 of 2169 African American individuals (as of 2/6/14). It is also reported in dbSNP (rs 121912998), though this seems to point to the NHLBI data. It was also seen in 4 of 1094 individuals in the 1000 genomes low coverage data. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 03, 2015 | p.Val30Met in exon 1 of DSP: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals, including several primates, have a methionine (Met) at this position. This strongly argues against a disease causing role, though a modifyin g effect cannot be excluded. In addition, it has been identified in 0.6% (57/99 98) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs12192998). Of note, this variant has been publ ished by several studies (http://arvcdatabase.info/), though the data provided b y these studies is uninformative. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2021 | Variant summary: DSP c.88G>A (p.Val30Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 212604 control chromosomes, predominantly at a frequency of 0.0043 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.88G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Yang_2006, Bauce_2010, Xu_2010, Rasmussen_2013, Rasmussen_2013, Bhonsale_2013, Rigato_2013). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Rasmussen_2012). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=9, VUS n=3). Based on the evidence outlined above, the variant was classified as benign. - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Uncertain significance, no assertion criteria provided | literature only | OMIM | Sep 15, 2006 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Cardiomyopathy Pathogenic:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 14, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 27, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences | Mar 27, 2015 | - - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jun 25, 2015 | - - |
Right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 13, 2013 | - - |
Keratosis palmoplantaris striata 2 Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Lethal acantholytic epidermolysis bullosa Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Woolly hair-skin fragility syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 30, 2018 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
DSP-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 12, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at