chr6-7576386-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_004415.4(DSP):c.2723G>A(p.Arg908His) variant causes a missense change. The variant allele was found at a frequency of 0.000882 in 1,614,076 control chromosomes in the GnomAD database, including 9 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. R908L) 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 | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2723G>A | p.Arg908His | missense_variant | 19/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.2723G>A | p.Arg908His | missense_variant | 19/24 | ||
DSP | NM_001008844.3 | c.2723G>A | p.Arg908His | missense_variant | 19/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2723G>A | p.Arg908His | missense_variant | 19/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.2723G>A | p.Arg908His | missense_variant | 19/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.2723G>A | p.Arg908His | missense_variant | 19/24 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000795 AC: 121AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00115 AC: 289AN: 251322Hom.: 1 AF XY: 0.00115 AC XY: 156AN XY: 135828
GnomAD4 exome AF: 0.000891 AC: 1302AN: 1461820Hom.: 9 Cov.: 34 AF XY: 0.000941 AC XY: 684AN XY: 727214
GnomAD4 genome AF: 0.000795 AC: 121AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.000833 AC XY: 62AN XY: 74436
ClinVar
Submissions by phenotype
not provided Benign:7
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | DSP: BP4, BS2 - |
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 | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 19, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 27, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Uncertain:1Benign:4
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 26, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Arg908His varia nt in DSP has been reported in 2 individuals with ARVC, but did not segregate wi th clinical features of ARVC in 1 relative (Quarta 2011). In addition, this vari ant has now been identified by our laboratory 5 individuals with various clinica l features (1 with RCM, 1 with LVH and RV dyskinesis, 1 with ARVC, 1 with LVNC and 1 with DCM and LVNC). It has also been identified in 0.2% (13/8600) of Europ ean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS/; dbSNP rs142494121). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide s trong support for or against an impact to the protein. In summary, the frequency of this variant and the presence in such variable phenotypes suggest that this variant is more likely benign, but additional information is needed to establish this with confidence. - |
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 | GeneDx | Feb 07, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 08, 2018 | Variant summary: DSP c.2723G>A (p.Arg908His) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 277668 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 107-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.2723G>A has been reported in the literature in individuals affected with Arrhythmia (Quarta_2011, Haas_2015, Ng_2013, Nunn_2016) including one family that showed lack of cosegregation with disease (Quarta_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign (4x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:2
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Sep 04, 2023 | - - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 19, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2018 | - - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Lethal acantholytic epidermolysis bullosa Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 12, 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 | Sep 12, 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 | Sep 12, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 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 | Oct 15, 2020 | 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