rs794728136

Positions:

• chr6-7555819-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_004415.4(DSP):​c.273del​(p.Glu92AsnfsTer2) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.90

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 20 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-7555819-CT-C is Pathogenic according to our data. Variant chr6-7555819-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.273del	p.Glu92AsnfsTer2	frameshift_variant, splice_region_variant	2/24	ENST00000379802.8
DSP	NM_001319034.2	c.273del	p.Glu92AsnfsTer2	frameshift_variant, splice_region_variant	2/24
DSP	NM_001008844.3	c.273del	p.Glu92AsnfsTer2	frameshift_variant, splice_region_variant	2/24
DSP	NM_001406591.1	c.273del	p.Glu92AsnfsTer2	frameshift_variant, splice_region_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.273del	p.Glu92AsnfsTer2	frameshift_variant, splice_region_variant	2/24	1	NM_004415.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 20, 2016

The p.Glu92fs variant in DSP has not been previously reported in individuals wit h cardiomyopathy, and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 92 and leads to a premature termination codon 2 amino acid s downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DSP gene is an established diseas e mechanism in individuals with ARVC and/or DCM. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu92f s variant is likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2014

Although the c.273delT mutation in the DSP gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Glutamic acid 92, changing it to an Asparagine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Glu92AsnfsX2. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the DSP gene have been reported in association with cardiomyopathy. In summary, c.273delT in the DSP gene is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: 0
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728136; hg19: chr6-7556052;