rs142885240

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004415.4(DSP):c.5218G>A(p.Glu1740Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,490 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: 𝑓 0.00096 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 5 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:20

Conservation

PhyloP100: 3.21

Publications

11 publications found

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]

DSP Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 8
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
keratosis palmoplantaris striata 2
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
skin fragility-woolly hair-palmoplantar keratoderma syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
lethal acantholytic epidermolysis bullosa
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
striate palmoplantar keratoderma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe dermatitis-multiple allergies-metabolic wasting syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

DSP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08162171).

BP6

Variant 6-7581408-G-A is Benign according to our data. Variant chr6-7581408-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44926.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000959 (146/152286) while in subpopulation AMR AF = 0.00229 (35/15296). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.5218G>A	p.Glu1740Lys	missense_variant	Exon 23 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.4050+1168G>A		intron_variant	Intron 23 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.3583-1234G>A		intron_variant	Intron 23 of 23		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.5218G>A	p.Glu1740Lys	missense_variant	Exon 23 of 24	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.000959

AC:

146

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00142

AC:

356

AN:

251104

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00158

AC:

2304

AN:

1461204

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1151

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.000360

AC:

AN:

33314

American (AMR)

AF:

0.00263

AC:

117

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000905

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0173

AC:

100

AN:

5768

European-Non Finnish (NFE)

AF:

0.00167

AC:

1858

AN:

1111826

Other (OTH)

AF:

0.00159

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

150

301

451

602

752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000959

AC:

146

AN:

152286

Hom.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41552

American (AMR)

AF:

0.00229

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00123

AC:

150

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:20

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:8

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 23, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21606396, 31395126, 26230511, 23861362, 26656175, 27153395, 27435932, 24503780, 30821013) -

Sep 07, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DSP: BP4, BS2 -

not specified

Benign:3

Apr 20, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu1740Lys variant in DSP is classified as likely benign because it has been identified in 0.2% (73/35312) of Latino and 0.18% (229/129084) of European chromosomes, including 1 homozygous individual by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in >10 individuals with a range of cardiomyopathy phenotypes (ARVC, DCM, HCM, RCM, Brugada syndrome, ventricular tachycardia), and it has segregated with Brugada syndrome in 1 affected relative from 1 family (Cox 2011, Allegue 2015, Bottillo 2016, LMM data). However, these diseases have different underlying molecular mechanisms, and furthermore, several of these probands were compound or double heterozygous with a presumed pathogenic variant. In summary, this variant is likely benign due to its elevated frequency in the general population, presence of phenotypes with different underlying molecular mechanisms in reported cases, as well as cases that had other more likely causative variants identified. ACMG/AMP Criteria applied: BS1, BP5, BP4. -

Feb 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:2

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy;C0018991:Hemiplegia;C0149931:Migraine

Uncertain:1

Nov 24, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Uncertain:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Criteria: BS1 -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Aug 01, 2016

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. -

Lethal acantholytic epidermolysis bullosa

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arrhythmogenic right ventricular dysplasia 8

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Aug 01, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Benign

-0.081

Eigen_PC

Benign

-0.072

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

M_CAP

Benign

0.033

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

PhyloP100

3.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.31

Sift

Uncertain

0.025

Sift4G

Benign

0.13

Polyphen

0.96

Vest4

0.71

MVP

0.77

MPC

0.34

ClinPred

0.034

GERP RS

5.1

Varity_R

0.14

gMVP

0.27

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over