rs2076299

Positions:

• chr6-7580725-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004415.4(DSP):​c.4535A>G​(p.Tyr1512Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0735 in 1,613,944 control chromosomes in the GnomAD database, including 8,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2425 hom., cov: 32)
  • Exomes 𝑓: 0.067 (6551 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18
• Conservation: PhyloP100: 0.852

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002193749).
• BP6: Variant 6-7580725-A-G is Benign according to our data. Variant chr6-7580725-A-G is described in ClinVar as [Benign]. Clinvar id is 44915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7580725-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.4535A>G	p.Tyr1512Cys	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4050+485A>G		intron_variant			NP_001305963.1
DSP	NM_001008844.3	c.3582+953A>G		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.4535A>G	p.Tyr1512Cys	missense_variant	23/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3582+953A>G		intron_variant		1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4050+485A>G		intron_variant				ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20929 AN: 152112 Hom.: 2415 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.118 AC: 29557 AN: 249902 Hom.: 2877 AF XY: 0.109 AC XY: 14733 AN XY: 135298

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.0842

Gnomad EAS exome AF: 0.291

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0842

GnomAD4 exome AF: 0.0667 AC: 97568 AN: 1461714 Hom.: 6551 Cov.: 33 AF XY: 0.0670 AC XY: 48746 AN XY: 727148

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.0867

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.0643

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0904

GnomAD4 genome AF: 0.138 AC: 20977 AN: 152230 Hom.: 2425 Cov.: 32 AF XY: 0.141 AC XY: 10507 AN XY: 74426

Gnomad4 AFR AF: 0.289

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.0922

Gnomad4 EAS AF: 0.283

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.0644

Gnomad4 NFE AF: 0.0378

Gnomad4 OTH AF: 0.136

Alfa AF: 0.0645 Hom.: 1775

Bravo AF: 0.152

TwinsUK AF: 0.0407 AC: 151

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.271 AC: 1193

ESP6500EA AF: 0.0442 AC: 380

ExAC AF: 0.115 AC: 13963

Asia WGS AF: 0.210 AC: 729 AN: 3478

EpiCase AF: 0.0397

EpiControl AF: 0.0393

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 03, 2012	Tyr1512Cys in exon 23 of DSP: This variant is not expected to have clinical sign ificance because it has been identified in 26% (983/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs2076299). Tyr1512Cys in exon 23 of DSP (rs2076299; allele frequency = 26%, 983/3738) ** -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 29.544% in ExAC) based on the frequency threshold of 0.5% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -
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	This variant is associated with the following publications: (PMID: 27153395, 25445213, 19863551) -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

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

- -

Lethal acantholytic epidermolysis bullosa 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. -

Woolly hair-skin fragility syndrome 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. -

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.45	P
Vest4		0.057
MPC		0.27
ClinPred		0.0080	T
GERP RS		1.8
Varity_R		0.046
gMVP		0.19

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: rs2076299; hg19: chr6-7580958; COSMIC: COSV65792806;