rs397517390

Positions:

• chr18-31082266-G-GT

Variant summary

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

The NM_024422.6(DSC2):​c.1234dupA​(p.Thr412fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.51

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 18-31082266-G-GT is Pathogenic according to our data. Variant chr18-31082266-G-GT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46164.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1234dupA	p.Thr412fs	frameshift_variant	9/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1234dupA	p.Thr412fs	frameshift_variant	9/17		NP_004940.1
DSC2	NM_001406506.1	c.805dupA	p.Thr269fs	frameshift_variant	9/16		NP_001393435.1
DSC2	NM_001406507.1	c.805dupA	p.Thr269fs	frameshift_variant	9/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1234dupA	p.Thr412fs	frameshift_variant	9/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1234dupA	p.Thr412fs	frameshift_variant	9/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.805dupA	p.Thr269fs	frameshift_variant	10/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.805dupA	p.Thr269fs	frameshift_variant	9/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2023

Identified in two siblings with ARVC, however, diagnostic criteria is unclear and functional studies were not performed (PMID: 22458570); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 22458570) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 13, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Thr412fs va riant in DSC2 has been reported in 1 individual with ARVC and 1 affected relativ e (Rajkumar 2012), and was not identified in large population studies. This vari ant has now been identified by our laboratory in 2 individuals with ARVC from on e family (this individual's sons). These individuals carried a second, possibly disease-causing variant, which was also detected in isolation in an affected rel ative. This frameshift variant is predicted to alter the protein?s amino acid se quence beginning at position 412 and lead to a premature termination codon 3 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants in DSC2 are known to be involved in t he etiology of ARVC. Although this data supports that the Thr412fs variant may b e pathogenic, additional studies are needed to fully assess its clinical signifi cance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517390; hg19: chr18-28662232;