rs142078450

Positions:

• chr6-7584884-G-A
• chr6-7584884-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_004415.4(DSP):​c.7622G>A​(p.Arg2541Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 4.49

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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3358029).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.7622G>A	p.Arg2541Lys	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.6293G>A	p.Arg2098Lys	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.5825G>A	p.Arg1942Lys	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.7622G>A	p.Arg2541Lys	missense_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.5825G>A	p.Arg1942Lys	missense_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.6293G>A	p.Arg2098Lys	missense_variant	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251490 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461894 Hom.: 0 Cov.: 36 AF XY: 0.0000316 AC XY: 23 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000594 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 10, 2023	This missense variant replaces arginine with lysine at codon 2541 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 21723241, 24070718). However, this variant did not segregate with disease in multiple individuals from one family (PMID: 20129281). This variant has been identified in 5/282902 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 27, 2015

The p.Arg2541Lys variant in DSP has been reported in 1 individual with ARVC (Bau ce 2010, Bauce 2011, Rigato 2013). The variant segregated with disease in 3 affe cted family members (including 2 obligate carriers); however, another affected r elative did not carry the variant (Bauce 2010). This variant has been identified in 3/66740 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs142078450). Arginine (Arg) at position 2541 is not conserved evolution and 4 mammals carry a lysine (Lys), suggesting that t his change may be tolerated. In summary, the clinical significance of the p.Arg2 541Lys variant is uncertain due to conflicting data. -

Lethal acantholytic epidermolysis bullosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Woolly hair-skin fragility syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 27, 2016

The DSP c.7622G>A (p.Arg2541Lys) variant is a missense variant that has been reported in four studies, where it was found in six individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), including in a compound heterozygous state in two individuals and in a heterozygous state in four (Bauce et al. 2010; Bauce et al. 2011; Rigato et al. 2013; Zorzi et al. 2015). The variant was also found in three unaffected individuals from the family described in Bauce et al. (2010); these individuals ranged in age from 20 to 30 years. Their unaffected status could represent decreased penetrance due to their ages. In the same family, of the three known or obligate carriers of the variant, one suffered sudden death at age 45, one affected female died of heart failure at age 64, and one was diagnosed at age 37. Zorzi et al. (2015) conducted a follow-up study and evaluated data from the individuals described by Rigato et al. (2013); one individual with this variant experienced cardiac arrest. The p.Arg2541Lys variant was absent from over 1100 control alleles but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg2541Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for arrhythmogenic right ventricular cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2020

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 228649; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 24125834, 24070718, 21723241, 26138720, 23911551, 20129281) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The p.R2541K variant (also known as c.7622G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 7622. The arginine at codon 2541 is replaced by lysine, an amino acid with highly similar properties. This variant was reported in a proband with arrhythmogenic right ventricular cardiomyopathy (ARVC), as well as in at least two family members with ARVC; however, this variant was not detected in another family member with ARVC, and at least two unaffected carriers were reported in this family (Bauce B et al. Heart Rhythm, 2010 Jan;7:22-9; Rigato I et al. Circ Cardiovasc Genet, 2013 Dec;6:533-42; Zorzi A et al. Europace, 2016 Jul;18:1086-94). This variant was also detected in one participant from an electronics medical record cohort, who did not have an ARVC diagnosis but clinical details were otherwise limited (Haggerty CM et al. Genet Med, 2017 11;19:1245-1252). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.46	N;.
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.57	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.51	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;.
Vest4		0.66
MutPred		0.81		Gain of ubiquitination at R2541 (P = 0.03);.;
MVP		0.92
MPC		0.22
ClinPred		0.26	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.26

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: rs142078450; hg19: chr6-7585117;