chr6-7575454-C-T

Position:

chr6-7575454-C-T

Variant summary

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

The NM_004415.4(DSP):c.2596C>T(p.Arg866Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R866H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: 4.65

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 links:

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=0.026894003).

BP6

Variant 6-7575454-C-T is Benign according to our data. Variant chr6-7575454-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44876.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=2, Benign=2}. Variant chr6-7575454-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSP	NM_004415.4 linkuse as main transcript	c.2596C>T	p.Arg866Cys	missense_variant	18/24	ENST00000379802.8
DSP	NM_001319034.2 linkuse as main transcript	c.2596C>T	p.Arg866Cys	missense_variant	18/24
DSP	NM_001008844.3 linkuse as main transcript	c.2596C>T	p.Arg866Cys	missense_variant	18/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.2596C>T	p.Arg866Cys	missense_variant	18/24	1	NM_004415.4	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.2596C>T	p.Arg866Cys	missense_variant	18/24	1		A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.2596C>T	p.Arg866Cys	missense_variant	18/24			A2
DSP	ENST00000684395.1 linkuse as main transcript	n.1237C>T		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

293

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00681

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000497

AC:

125

AN:

251416

Hom.:

AF XY:

0.000442

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000172

AC:

251

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00600

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.00193

AC:

294

AN:

152230

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00681

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000454

Hom.:

Bravo

AF:

0.00217

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000610

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	This variant is associated with the following publications: (PMID: 21636032, 24503780) -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2017	Variant summary: The DSP c.2596C>T (p.Arg866Cys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The variant resides outside of any known functional domain (InterPro). This variant was found in 75/122246 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.006826 (71/10402). This frequency is about 683 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this is likely a benign polymorphism found primarily in populations of African origin. 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 13, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 20, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 23, 2015

p.Arg866Cys in exon 18 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (71/10402) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs142429411). -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Woolly hair-skin fragility syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Epidermolysis bullosa simplex due to plakophilin deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2019

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

Pathogenic

0.89

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.90

MVP

0.79

MPC

0.96

ClinPred

0.088

GERP RS

5.1

Varity_R

0.69

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over