rs886038929

chr6-7585448-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_004415.4(DSP):c.8188del(p.Gln2730SerfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F2729F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.956

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 7 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7585448-TC-T is Pathogenic according to our data. Variant chr6-7585448-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263803.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.8188del	p.Gln2730SerfsTer16	frameshift_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.6859del	p.Gln2287SerfsTer16	frameshift_variant	24/24
DSP	NM_001008844.3	c.6391del	p.Gln2131SerfsTer16	frameshift_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.8188del	p.Gln2730SerfsTer16	frameshift_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.6391del	p.Gln2131SerfsTer16	frameshift_variant	24/24	1		A2
DSP	ENST00000710359.1	c.6859del	p.Gln2287SerfsTer16	frameshift_variant	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2019

The c.8188delC variant, located in coding exon 24 of the DSP gene, results from a deletion of one nucleotide at nucleotide position 8188, causing a translational frameshift with a predicted alternate stop codon (p.Q2670Sfs*16). This alteration has been observed in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy cohorts (Castelletti S et al. Int. J. Cardiol., 2017 Dec;249:268-273; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Frameshifts are typically deleterious in nature, and while this frameshift occurs at the 3' terminus of DSP and is not expected to trigger nonsense-mediated mRNA decay, the last 140 amino acids of the protein (including two plectin domains and a plakin repeat region) are removed. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 05, 2022

This sequence change creates a premature translational stop signal (p.Gln2730Serfs*16) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 142 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 arrythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (PMID: 27532257, 28527814). ClinVar contains an entry for this variant (Variation ID: 263803). This variant disrupts the C-terminus of the DSP protein. Other variant(s) that disrupt this region (p.Arg2834His) have been observed in individuals with DSP-related conditions (PMID: 16917092). This suggests that this may be a clinically significant region of the protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs886038929; hg19: chr6-7585681;