6-7583872-C-T

Position:

• chr6-7583872-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_004415.4(DSP):​c.6610C>T​(p.Gln2204Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.13

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_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.6610C>T	p.Gln2204Ter	stop_gained	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.5281C>T	p.Gln1761Ter	stop_gained	24/24		NP_001305963.1
DSP	NM_001008844.3	c.4813C>T	p.Gln1605Ter	stop_gained	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.6610C>T	p.Gln2204Ter	stop_gained	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.4813C>T	p.Gln1605Ter	stop_gained	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.5281C>T	p.Gln1761Ter	stop_gained	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DSP-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

The DSP c.6610C>T variant is predicted to result in premature protein termination (p.Gln2204*). This variant was reported in the compound heterozygous state in a pair of monozygotic twins with lethal acantholytic epidermolysis bullosa, while the heterozygous carriers in this family were reported asymptomatic (Kim et al. 2017. PubMed ID: 28442525). This variant has not been reported in a large population database, indicating this variant is rare. This variant is located in the large terminal exon and multiple downstream loss-of-function variants have been documented in individuals with autosomal dominant DSP-associated cardiomyopathy or arrhythmogenic right ventricular dysplasia (Fressart et al. 2010. PubMed ID: 20400443; Tables S1 and S2, Smith et al. 2020. PubMed ID: 32372669; Table S1, Wang et al. 2022. PubMed ID: 34352074). In summary, this variant is interpreted as pathogenic for autosomal dominant and recessive DSP-associated disorders. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 02, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln2204X variant in DSP has not been previously reported in individuals with cardiomyopat hy and was absent from large population studies. This nonsense variant leads to a premature termination codon within the last exon. Nonsense variants are well r eported patients with ARVC (http://arvcdatabase.info/) and this type of variant is generally expected to lead to nonsense medicated mRNA decay (NMD), resulting in loss of function. However, this is less likely in the last exon and therefore the effect of this variant on the protein is not clear. Some evidence for a rol e in ARVC comes from reports of homozygous truncating variants in the last exon in individuals with Carvajal syndrome and/or acantholytic epidermolysis bullosa (Cheong 2005, Jonkman 2005, Rasmussen 2013), though it is less clear if heterozy gous carriers exhibit any features. In summary, while there is some suspicion f or a pathogenic role, the clinical significance of the p.Gln2204X variant is unc ertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.83	D
MutationTaster	Benign	1.0	D;D
Vest4		0.94
GERP RS		5.6

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: rs876657798; hg19: chr6-7584105;