rs200421954

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_004415.4(DSP):c.4775A>G(p.Lys1592Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 6.10

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 6-7580965-A-G is Benign according to our data. Variant chr6-7580965-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188466.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.4775A>G	p.Lys1592Arg	missense_variant	Exon 23 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.4050+725A>G		intron_variant	Intron 23 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.3582+1193A>G		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.4775A>G	p.Lys1592Arg	missense_variant	Exon 23 of 24	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000232

AC:

AN:

250148

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000372

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000283

AC:

413

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

200

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000343

AC:

381

AN:

1111992

Other (OTH)

AF:

0.000199

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000158

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000300

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 07, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with HCM, ARVC, and sudden unexplained death (Cox et al., 2011; Bagnall et al., 2014; Bhonsale et al., 2015; Lopes et al., 2015); Reported in a male with sudden cardiac arrest at 28 years old, unrelated to exercise; this individual had no clear cardiac phenotype and also harbored a novel splice site variant in the TTN gene (Asatryan et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 24440382, 25616645, 21606396, 27153395, 30975432) -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DSP: PM2, BP4 -

Cardiomyopathy

Uncertain:1Benign:1

Mar 29, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces lysine with arginine at codon 1592 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396), in an individual with sudden death (PMID: 24440382), and in a sudden cardiac arrest survivor (PMID: 30975432). This variant occurs at an elevated allele frequency in the general population and has been identified in 65/281550 chromosomes by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jun 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DSP c.4775A>G (p.Lys1592Arg) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00023 in 250148 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 41 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.4775A>G has been observed in one individual affected with ARVD, one individual with a history of syncope and one individual with sudden cardiac arrest (Cox_2011, Bagnall_2014, Asatryan_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been observed in an individual undergoing evaluation on a Familial Arrhythmia Panel at our laboratory (KCNQ1 c.1124_1127delTTCA, p.Ile375fs, Long QT syndrome), providing supporting evidence for a benign role. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30975432, 24440382, 21606396, 27153395). ClinVar contains an entry for this variant (Variation ID: 188466). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

May 03, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

-0.073

Eigen_PC

Benign

0.099

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

PhyloP100

6.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.37

REVEL

Pathogenic

0.71

Sift

Benign

0.39

Sift4G

Benign

0.53

Polyphen

0.56

Vest4

0.75

MVP

0.80

MPC

0.18

ClinPred

0.063

GERP RS

4.8

Varity_R

0.049

gMVP

0.22

Mutation Taster

=36/64

disease causing

(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