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rs139071827

chr6-7574705-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

The NM_004415.4(DSP):c.2346C>T(p.Asp782=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,118 control chromosomes in the GnomAD database, including 2 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 0.0012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

DSP
NM_004415.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:12

Conservation

PhyloP100: 1.01
Variant links:
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 Likely_benign. Variant got -4 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-7574705-C-T is Benign according to our data. Variant chr6-7574705-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44873.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3, Benign=1}. Variant chr6-7574705-C-T is described in Lovd as [Benign]. Variant chr6-7574705-C-T is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.01 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DSPNM_004415.4 linkuse as main transcriptc.2346C>T p.Asp782= synonymous_variant 17/24 ENST00000379802.8
DSPNM_001319034.2 linkuse as main transcriptc.2346C>T p.Asp782= synonymous_variant 17/24
DSPNM_001008844.3 linkuse as main transcriptc.2346C>T p.Asp782= synonymous_variant 17/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.2346C>T p.Asp782= synonymous_variant 17/241 NM_004415.4 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.2346C>T p.Asp782= synonymous_variant 17/241 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.2346C>T p.Asp782= synonymous_variant 17/24 A2
DSPENST00000684395.1 linkuse as main transcriptn.987C>T non_coding_transcript_exon_variant 4/5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00125
AC:
190
AN:
152144
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000386
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00132
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00209
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00132
AC:
333
AN:
251366
Hom.:
1
AF XY:
0.00147
AC XY:
200
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.000198
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00150
Gnomad FIN exome
AF:
0.00111
Gnomad NFE exome
AF:
0.00212
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.00155
AC:
2273
AN:
1461856
Hom.:
2
Cov.:
32
AF XY:
0.00160
AC XY:
1164
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.000306
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00150
Gnomad4 FIN exome
AF:
0.00127
Gnomad4 NFE exome
AF:
0.00177
Gnomad4 OTH exome
AF:
0.00132
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00125
AC:
190
AN:
152262
Hom.:
0
Cov.:
33
AF XY:
0.00120
AC XY:
89
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.000385
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00132
Gnomad4 NFE
AF:
0.00209
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00162
Hom.:
0
Bravo
AF:
0.00108
EpiCase
AF:
0.00147
EpiControl
AF:
0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 27, 2023- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2023DSP: BP4, BP7 -
not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 20, 2017Asp782Asp in exon 17 of DSP: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.2% (132/66740) of European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs139071827). -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Lethal acantholytic epidermolysis bullosa Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 14, 2018- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 24, 2016This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
Cadd
Benign
9.1
Dann
Benign
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139071827; hg19: chr6-7574938; COSMIC: COSV65790835; API