6-7583062-C-T

Position:

• chr6-7583062-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.5800C>T​(p.Arg1934Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1934R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.634

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 Pathogenic. Variant got 18 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 89 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7583062-C-T is Pathogenic according to our data. Variant chr6-7583062-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7583062-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.5800C>T	p.Arg1934Ter	stop_gained	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.4471C>T	p.Arg1491Ter	stop_gained	24/24
DSP	NM_001008844.3	c.4003C>T	p.Arg1335Ter	stop_gained	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5800C>T	p.Arg1934Ter	stop_gained	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.4003C>T	p.Arg1335Ter	stop_gained	24/24	1		A2
DSP	ENST00000710359.1	c.4471C>T	p.Arg1491Ter	stop_gained	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31402444, 27532257, 31514951, 30919684, 20738328, 19924139, 28416588, 17531221, 16175511, 20400443, 28527814) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 26, 2022	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change creates a premature translational stop signal (p.Arg1934*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 938 amino acid(s) of the DSP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with DSP-related conditions (PMID: 16175511, 28416588, 30919684). ClinVar contains an entry for this variant (Variation ID: 16843). This variant disrupts a region of the DSP protein in which other variant(s) (p.Gln2730Serfs*16) have been determined to be pathogenic (PMID: 27532257, 28527814). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Lethal acantholytic epidermolysis bullosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.20	N
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		-0.41

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: rs121912996; hg19: chr6-7583295; COSMIC: COSV105828761;