6-7577007-CA-C

Position:

• chr6-7577007-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004415.4(DSP):​c.2848del​(p.Ile950LeufsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.70

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7577007-CA-C is Pathogenic according to our data. Variant chr6-7577007-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 855123.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-7577007-CA-C is described in Lovd as [Likely_pathogenic]. Variant chr6-7577007-CA-C is described in Lovd as [Pathogenic]. Variant chr6-7577007-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.2848del	p.Ile950LeufsTer27	frameshift_variant	20/24	ENST00000379802.8
DSP	NM_001319034.2	c.2848del	p.Ile950LeufsTer27	frameshift_variant	20/24
DSP	NM_001008844.3	c.2848del	p.Ile950LeufsTer27	frameshift_variant	20/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.2848del	p.Ile950LeufsTer27	frameshift_variant	20/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.2848del	p.Ile950LeufsTer27	frameshift_variant	20/24	1		A2
DSP	ENST00000710359.1	c.2848del	p.Ile950LeufsTer27	frameshift_variant	20/24			A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459802 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726010

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

Invitae

Dec 06, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 25157032). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile950Leufs*27) in the DSP gene. It is expected to result in an absent or disrupted protein product. -

Arrhythmogenic cardiomyopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University

Jan 10, 2023

- -

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: rs397516927; hg19: chr6-7577240;