6-7585734-G-C

Position:

• chr6-7585734-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_004415.4(DSP):​c.8472G>C​(p.Gly2824=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,611,304 control chromosomes in the GnomAD database, including 397,692 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 0.69 (36549 hom., cov: 32)
  • Exomes 𝑓: 0.70 (361143 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:25
• Conservation: PhyloP100: -0.0450

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 6-7585734-G-C is Benign according to our data. Variant chr6-7585734-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44967.We mark this variant Likely_benign, oryginal submissions are: {Benign=18, Uncertain_significance=1}. Variant chr6-7585734-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.045 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.8472G>C	p.Gly2824=	synonymous_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.7143G>C	p.Gly2381=	synonymous_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.6675G>C	p.Gly2225=	synonymous_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8472G>C	p.Gly2824=	synonymous_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.6675G>C	p.Gly2225=	synonymous_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.7143G>C	p.Gly2381=	synonymous_variant	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes AF: 0.691 AC: 104985 AN: 151956 Hom.: 36528 Cov.: 32

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.711

GnomAD3 exomes AF: 0.714 AC: 177513 AN: 248526 Hom.: 63618 AF XY: 0.715 AC XY: 96376 AN XY: 134738

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.750

Gnomad ASJ exome AF: 0.745

Gnomad EAS exome AF: 0.804

Gnomad SAS exome AF: 0.720

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.703 AC: 1025199 AN: 1459228 Hom.: 361143 Cov.: 84 AF XY: 0.704 AC XY: 510788 AN XY: 725680

Gnomad4 AFR exome AF: 0.629

Gnomad4 AMR exome AF: 0.752

Gnomad4 ASJ exome AF: 0.746

Gnomad4 EAS exome AF: 0.814

Gnomad4 SAS exome AF: 0.722

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.698

Gnomad4 OTH exome AF: 0.711

GnomAD4 genome AF: 0.691 AC: 105059 AN: 152076 Hom.: 36549 Cov.: 32 AF XY: 0.694 AC XY: 51573 AN XY: 74336

Gnomad4 AFR AF: 0.638

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.752

Gnomad4 EAS AF: 0.796

Gnomad4 SAS AF: 0.725

Gnomad4 FIN AF: 0.649

Gnomad4 NFE AF: 0.700

Gnomad4 OTH AF: 0.708

Alfa AF: 0.697 Hom.: 11999

Bravo AF: 0.697

EpiCase AF: 0.728

EpiControl AF: 0.717

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:25

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2011	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 09, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

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	Apr 08, 2018	- -

Lethal acantholytic epidermolysis bullosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 12, 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	- -

Arrhythmogenic right ventricular dysplasia 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Phosphorus, Inc.	Aug 01, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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. -

DSP-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2023

This variant is classified as 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
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.5
DANN	Benign	0.70

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: rs2744380; hg19: chr6-7585967; COSMIC: COSV60939587; COSMIC: COSV60939587;