rs149070106
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_004415.4(DSP):c.6678T>A(p.Gly2226=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,134 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).
Frequency
Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 3 hom. )
Consequence
DSP
NM_004415.4 synonymous
NM_004415.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.93
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 Benign. Variant got -10 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 6-7583940-T-A is Benign according to our data. Variant chr6-7583940-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44941.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=3}. Variant chr6-7583940-T-A is described in Lovd as [Benign]. Variant chr6-7583940-T-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.93 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.6678T>A | p.Gly2226= | synonymous_variant | 24/24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.5349T>A | p.Gly1783= | synonymous_variant | 24/24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.4881T>A | p.Gly1627= | synonymous_variant | 24/24 | NP_001008844.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.6678T>A | p.Gly2226= | synonymous_variant | 24/24 | 1 | NM_004415.4 | ENSP00000369129 | P2 | |
| DSP | ENST00000418664.2 | c.4881T>A | p.Gly1627= | synonymous_variant | 24/24 | 1 | ENSP00000396591 | A2 | ||
| DSP | ENST00000710359.1 | c.5349T>A | p.Gly1783= | synonymous_variant | 24/24 | ENSP00000518230 | A2 |
Frequencies
GnomAD3 genomes 0.00131 AC: 200AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00123 AC: 310AN: 251424Hom.: 2 AF XY: 0.00127 AC XY: 173AN XY: 135882
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GnomAD4 exome AF: 0.00122 AC: 1783AN: 1461868Hom.: 3 Cov.: 32 AF XY: 0.00118 AC XY: 855AN XY: 727232
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GnomAD4 genome 0.00131 AC: 200AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114AN XY: 74460
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:13
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:6
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2017 | Variant summary: The DSP c.6678T>A (p.Gly2226Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 174/121392 control chromosomes (1 homozygote) at a frequency of 0.0014334, which is approximately 57 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this variant is likely a benign polymorphism. Multiple clinical diagnostic laboratories/reputable databases as well as a publication classified this variant as likely benign/benign. Taken together, this variant is classified as benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 26, 2020 | - - |
| 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 | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | DSP: BP4, BP7 - |
not specified Benign:4
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Gly2226Gly in exon 24 of DSP: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (9/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs149070106). - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Lethal acantholytic epidermolysis bullosa Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Woolly hair-skin fragility syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Cardiomyopathy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 14, 2018 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 23, 2015 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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