chr6-7585563-C-G
Position:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_004415.4(DSP):āc.8301C>Gā(p.Thr2767Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,614,146 control chromosomes in the GnomAD database, including 5 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: š 0.00047 ( 0 hom., cov: 32)
Exomes š: 0.00043 ( 5 hom. )
Consequence
DSP
NM_004415.4 synonymous
NM_004415.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.560
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
Variant 6-7585563-C-G is Benign according to our data. Variant chr6-7585563-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36025.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3, Benign=5}. Variant chr6-7585563-C-G is described in Lovd as [Benign]. Variant chr6-7585563-C-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.56 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 5 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.8301C>G | p.Thr2767Thr | synonymous_variant | 24/24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.6972C>G | p.Thr2324Thr | synonymous_variant | 24/24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.6504C>G | p.Thr2168Thr | synonymous_variant | 24/24 | NP_001008844.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.8301C>G | p.Thr2767Thr | synonymous_variant | 24/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
| DSP | ENST00000418664.2 | c.6504C>G | p.Thr2168Thr | synonymous_variant | 24/24 | 1 | ENSP00000396591.2 | |||
| DSP | ENST00000710359.1 | c.6972C>G | p.Thr2324Thr | synonymous_variant | 24/24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes 0.000460 AC: 70AN: 152158Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
70
AN:
152158
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000648 AC: 163AN: 251380Hom.: 0 AF XY: 0.000692 AC XY: 94AN XY: 135874
GnomAD3 exomes
AF:
AC:
163
AN:
251380
Hom.:
AF XY:
AC XY:
94
AN XY:
135874
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000428 AC: 625AN: 1461870Hom.: 5 Cov.: 37 AF XY: 0.000440 AC XY: 320AN XY: 727240
GnomAD4 exome
AF:
AC:
625
AN:
1461870
Hom.:
Cov.:
37
AF XY:
AC XY:
320
AN XY:
727240
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000466 AC: 71AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74450
GnomAD4 genome
AF:
AC:
71
AN:
152276
Hom.:
Cov.:
32
AF XY:
AC XY:
34
AN XY:
74450
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
1
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:13
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:4
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 25, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2015 | p.Thr2767Thr 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% (55/66560) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs145362059). - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2014 | 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. - |
not provided Benign:3
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| 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 | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | DSP: BP4, BP7 - |
Cardiomyopathy Benign:2
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 11, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 10, 2023 | - - |
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 cardiomyopathy with wooly hair and keratoderma Benign:1
| Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
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 24, 2024 | - - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 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. - |
DSP-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 21, 2024 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at