6-7576436-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_004415.4(DSP):c.2773C>T(p.Arg925Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,614,028 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. R925Q) has been classified as Likely benign.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2773C>T | p.Arg925Trp | missense_variant | 19/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.2773C>T | p.Arg925Trp | missense_variant | 19/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.2773C>T | p.Arg925Trp | missense_variant | 19/24 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2773C>T | p.Arg925Trp | missense_variant | 19/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.2773C>T | p.Arg925Trp | missense_variant | 19/24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.2773C>T | p.Arg925Trp | missense_variant | 19/24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.00127 AC: 193AN: 152106Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000398 AC: 100AN: 251364Hom.: 1 AF XY: 0.000420 AC XY: 57AN XY: 135862
GnomAD4 exome AF: 0.000157 AC: 230AN: 1461804Hom.: 2 Cov.: 34 AF XY: 0.000158 AC XY: 115AN XY: 727206
GnomAD4 genome AF: 0.00127 AC: 193AN: 152224Hom.: 1 Cov.: 33 AF XY: 0.00124 AC XY: 92AN XY: 74434
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | DSP: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 23, 2020 | The DSP c.2773C>T, p.Arg925Trp variant (rs145933612), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 44881). This variant is found in the African population with an allele frequency of 0.2% (108/24,952 alleles) in the Genome Aggregation Database. The arginine at codon 925 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg925Trp variant is uncertain at this time. Gene statement: Pathogenic variants in DSP are associated with autosomal dominant arrhythmogenic right ventricular dysplasia 8 (MIM: 607450), dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (MIM: 615821), and keratosis palmoplantaris striata II (MIM: 612908), and autosomal recessive dilated cardiomyopathy with woolly hair and keratoderma (MIM: 605676), lethal acantholytic epidermolysis bullosa (MIM: 609638), and skin fragility-woolly hair syndrome (MIM: 607655). - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2021 | This variant is associated with the following publications: (PMID: 25351510) - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Feb 17, 2025 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 09, 2015 | p.Arg925Trp in exon 19 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (45/10296) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs145933612). - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2017 | Variant summary: The DSP c.2773C>T (p.Arg925Trp) variant involves the alteration of a conserved nucleotide that is located in the Spectrin/alpha-actinin domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 140/277128 control chromosomes, including 1 homozygote, at a frequency of 0.0005052, which is approximately 51 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this variant is likely a benign polymorphism. Additionally, the variant was found in 105/24026 African control chromosomes, a frequency of 0.00437, which is approximately 437 times above the maximal expected allele frequency, suggesting it is most prevalent in this subpopulation and further supporting a benign impact of the variant. The variant has been cited in the literature without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign. - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 05, 2018 | - - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 24, 2015 | - - |
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | DSP NM_004415.3 exon 19 p.Arg925Trp (c.2773C>T): This variant has not been reported in the literature and is present in 0.4% (108/24952) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/6-7576669-C-T). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:44881). However, evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
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 | Jan 31, 2025 | - - |
Lethal acantholytic epidermolysis bullosa Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 22, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Woolly hair-skin fragility syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 22, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Arrhythmogenic right ventricular dysplasia 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 22, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 01, 2019 | This alteration is classified as likely 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, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 24, 2019 | 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