rs397514043

Positions:

• chr18-31074729-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024422.6(DSC2):​c.1841delG​(p.Ser614fs) 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0120

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 18-31074729-AC-A is Pathogenic according to our data. Variant chr18-31074729-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 31635.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-31074729-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1841delG	p.Ser614fs	frameshift_variant	12/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1841delG	p.Ser614fs	frameshift_variant	12/17		NP_004940.1
DSC2	NM_001406506.1	c.1412delG	p.Ser471fs	frameshift_variant	12/16		NP_001393435.1
DSC2	NM_001406507.1	c.1412delG	p.Ser471fs	frameshift_variant	12/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1841delG	p.Ser614fs	frameshift_variant	12/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1841delG	p.Ser614fs	frameshift_variant	12/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1412delG	p.Ser471fs	frameshift_variant	13/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1412delG	p.Ser471fs	frameshift_variant	12/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia, familial, 11, with mild palmoplantar keratoderma and woolly hair Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397514043; hg19: chr18-28654695;