6-7585276-C-T

Position:

• chr6-7585276-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000379802.8(DSP):​c.8014C>T​(p.Gln2672Ter) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP ENST00000379802.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.38

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 14 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 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7585276-C-T is Pathogenic according to our data. Variant chr6-7585276-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 419466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.8014C>T	p.Gln2672Ter	stop_gained	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.6685C>T	p.Gln2229Ter	stop_gained	24/24		NP_001305963.1
DSP	NM_001008844.3	c.6217C>T	p.Gln2073Ter	stop_gained	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8014C>T	p.Gln2672Ter	stop_gained	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.6217C>T	p.Gln2073Ter	stop_gained	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.6685C>T	p.Gln2229Ter	stop_gained	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

May 14, 2022

This sequence change creates a premature translational stop signal (p.Gln2672*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 200 amino acid(s) of the DSP protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 419466). This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic (Invitae). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2015

The Q2672X variant in the DSP gene has not been reported as a pathogenic variant or as a benignpolymorphism to our knowledge. Q2672X is predicted to result in a truncated protein product due to the lossof the last 200 amino acid residues and therefore cause loss of normal protein function. Other nonsensevariants in the DSP gene have been reported in HGMD in association with cardiomyopathy (Stenson P et al.,2014). Furthermore, the Q2672X variant was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. In summary, Q2672X in the DSP gene is interpreted as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D;D
Vest4		0.94
GERP RS		5.5

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: rs1064793890; hg19: chr6-7585509; COSMIC: COSV100672870; COSMIC: COSV100672870;