rs2076300

chr6-7584384-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004415.4(DSP):c.7122C>T(p.Thr2374=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,613,850 control chromosomes in the GnomAD database, including 89,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6708 hom., cov: 31)
  • Exomes 𝑓: 0.33 (82550 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -5.08

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-7584384-C-T is Benign according to our data. Variant chr6-7584384-C-T is described in ClinVar as [Benign]. Clinvar id is 44947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7584384-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.7122C>T	p.Thr2374=	synonymous_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.5793C>T	p.Thr1931=	synonymous_variant	24/24
DSP	NM_001008844.3	c.5325C>T	p.Thr1775=	synonymous_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.7122C>T	p.Thr2374=	synonymous_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.5325C>T	p.Thr1775=	synonymous_variant	24/24	1		A2
DSP	ENST00000710359.1	c.5793C>T	p.Thr1931=	synonymous_variant	24/24			A2

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42856 AN: 151926 Hom.: 6703 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.0811

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.288 AC: 72500 AN: 251380 Hom.: 11593 AF XY: 0.297 AC XY: 40368 AN XY: 135878

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.0651

Gnomad SAS exome AF: 0.257

Gnomad FIN exome AF: 0.331

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.330 AC: 482087 AN: 1461806 Hom.: 82550 Cov.: 61 AF XY: 0.330 AC XY: 240104 AN XY: 727200

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.0902

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.282 AC: 42867 AN: 152044 Hom.: 6708 Cov.: 31 AF XY: 0.280 AC XY: 20779 AN XY: 74320

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.0811

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.285

Alfa AF: 0.342 Hom.: 18467

Bravo AF: 0.273

Asia WGS AF: 0.152 AC: 531 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 07, 2007	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy Benign:2

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -

Lethal acantholytic epidermolysis bullosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Woolly hair-skin fragility syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Keratosis palmoplantaris striata 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2015

This alteration is classified as 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	-0.72
Cadd	Benign	0.12
Dann	Benign	0.65

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

Other links and lift over

dbSNP: rs2076300; hg19: chr6-7584617; COSMIC: COSV65791917;