Menu
GeneBe

rs147415451

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_004415.4(DSP):c.5178C>A(p.Asn1726Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000554 in 1,614,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N1726N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00057 ( 1 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18

Conservation

PhyloP100: -0.0320
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010507256).
BP6
Variant 6-7581368-C-A is Benign according to our data. Variant chr6-7581368-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178032.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=14, Uncertain_significance=1, Benign=1}. Variant chr6-7581368-C-A is described in Lovd as [Benign]. Variant chr6-7581368-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DSPNM_004415.4 linkuse as main transcriptc.5178C>A p.Asn1726Lys missense_variant 23/24 ENST00000379802.8
DSPNM_001008844.3 linkuse as main transcriptc.3583-1274C>A intron_variant
DSPNM_001319034.2 linkuse as main transcriptc.4050+1128C>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.5178C>A p.Asn1726Lys missense_variant 23/241 NM_004415.4 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.3583-1274C>A intron_variant 1 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.4050+1128C>A intron_variant A2

Frequencies

GnomAD3 genomes
AF:
0.000368
AC:
56
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00166
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000647
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000744
AC:
187
AN:
251336
Hom.:
1
AF XY:
0.000950
AC XY:
129
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00350
Gnomad FIN exome
AF:
0.000231
Gnomad NFE exome
AF:
0.000598
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000573
AC:
838
AN:
1461888
Hom.:
1
Cov.:
32
AF XY:
0.000741
AC XY:
539
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00336
Gnomad4 FIN exome
AF:
0.000337
Gnomad4 NFE exome
AF:
0.000442
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
AF:
0.000368
AC:
56
AN:
152296
Hom.:
0
Cov.:
32
AF XY:
0.000376
AC XY:
28
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000647
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000581
Hom.:
1
Bravo
AF:
0.000389
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000857
AC:
104
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:18
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:7
Likely benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute-- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 13, 2017Variant summary: The DSP c.5178C>A (p.Asn1726Lys) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant was found in 106/121670 control chromosomes at a frequency of 0.0008712, which is approximately 87 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this variant is likely a benign polymorphism. The variant has been reported 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. -
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2023DSP: BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 05, 2019This variant is associated with the following publications: (PMID: 23396983, 23861362, 28600387, 20829228, 31402444) -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not specified Benign:3
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingBlueprint GeneticsAug 06, 2015- -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 10, 2018proposed classification - variant undergoing re-assessment, contact laboratory -
Cardiomyopathy Benign:2
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioFeb 10, 2023- -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 07, 2018- -
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterresearchKlaassen Lab, Charite University Medicine BerlinJul 03, 2019- -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Lethal acantholytic epidermolysis bullosa Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 31, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaMay 31, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaMay 31, 2018This 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
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 13, 2018This alteration is classified as likely benign based on a combination of the following: 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 condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 04, 2022This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.44
Cadd
Benign
12
Dann
Benign
0.96
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.73
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.011
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
0.27
N
REVEL
Benign
0.10
Sift
Benign
0.46
T
Sift4G
Benign
1.0
T
Polyphen
0.49
P
Vest4
0.51
MutPred
0.13
Gain of ubiquitination at N1726 (P = 0.006);
MVP
0.62
MPC
0.70
ClinPred
0.036
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.097
gMVP
0.13

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: rs147415451; hg19: chr6-7581601; API