rs147000526

Positions:

• chr6-7584143-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS2

The NM_004415.4(DSP):​c.6881C>G​(p.Ala2294Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000794 in 1,614,152 control chromosomes in the GnomAD database, including 5 homozygotes. 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. A2294T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (5 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:15
• Conservation: PhyloP100: 7.91

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 Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.1640684).
• BP6: Variant 6-7584143-C-G is Benign according to our data. Variant chr6-7584143-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44943.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=3, Benign=1}. Variant chr6-7584143-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.6881C>G	p.Ala2294Gly	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.5552C>G	p.Ala1851Gly	missense_variant	24/24
DSP	NM_001008844.3	c.5084C>G	p.Ala1695Gly	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.6881C>G	p.Ala2294Gly	missense_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.5084C>G	p.Ala1695Gly	missense_variant	24/24	1		A2
DSP	ENST00000710359.1	c.5552C>G	p.Ala1851Gly	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000843 AC: 212 AN: 251492 Hom.: 2 AF XY: 0.000743 AC XY: 101 AN XY: 135920

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000949

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000813 AC: 1189 AN: 1461882 Hom.: 5 Cov.: 32 AF XY: 0.000765 AC XY: 556 AN XY: 727246

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000892

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74452

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000584 Hom.: 0

Bravo AF: 0.000876

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000848 AC: 103

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2021	This variant is associated with the following publications: (PMID: 25637381, 25820315, 26314686, 27153395, 23299917, 25616645, 26498160, 23861362, 25163546, 25351510, 26899768, 27896284, 21859740, 26220970) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jan 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 18, 2018	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 10, 2017	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 26, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of segregation in multiple cases we consider this variant a variant of uncertain significance, probably benign. The variant has been seen in at least 2 unrelated cases of DCM and 4 cases ARVC with failure to segregate in at least 4 cases. At least 7% of patients with autosomal dominant ARVC have been reported to have a mutation in the DSP gene (McNally E et al., 2009). The Ala2294Gly variant has been reported previously in two individuals with dilated cardiomyoapthy (Garcia-Pavia P et al., 2011). One of the probands was a 60 year old male, the other a 51 year old male. No segregation analysis was available. This was a cohort of 95 patients randomly selected from a cohort of 187 patients transplanted for DCM between 1993 and 2007. The authors did sequencing for plakophillin-2 (PKP2), desmoplakin (DSP), desmocollin-2 (DSC2), desmoglein (DSG2) and plakoglobin (JUP). They did not study other DCM genes. Garcia and Monserrat (2010, case presentation) reported this variant was identified in a proband with right ventricular dysfunction, whose father was also affected, but did not carry the variant. The proband carried three other variants in the tested ARVC genes. As part of the authors' review of this variant, they report this variant has been reported in an additional three families (Dr. Van der Zwaag, personal communication). In one of these families, a proband with ARVC had solely this variant and it failed to segregate with disease in the proband's mother who also had a clinical diagnosis of ARVC. Another family, the proband (72 years old) carried a second confirmed pathogenic mutation in DSP. In the third family, the variant was identified in the father of a male patient who died suddenly at age 25, although the patient did not have the variant and both were carrier of a confirmed pathogenic mutation in another gene. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The alanine at codon 2294 is conserved across species, as are neighboring amino acids. In total the variant has been seen in 3/6703 laboratory controls, published controls and individuals from publicly available population datasets. The variant was reported online in 3 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 1/30/14). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. This variant is listed in dbSNP: rs147000526. The variant was not observed in the following laboratory and published control samples: Not present in 200 control individuals (Garcia-Pavia P e al., 2011) -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 29, 2017	- -
Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Dec 01, 2015	- -

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

Likely 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

May 16, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 16, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 16, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 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	0.88
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.71
MVP		0.94
MPC		0.79
ClinPred		0.32	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.88
gMVP		0.78

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: rs147000526; hg19: chr6-7584376;