rs1060502989

chr18-31086635-A-AT

Variant summary

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

The NM_024422.6(DSC2):c.882_883insA(p.Phe295IlefsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L294L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -5.42

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 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 18-31086635-A-AT is Pathogenic according to our data. Variant chr18-31086635-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 410650.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.882_883insA	p.Phe295IlefsTer23	frameshift_variant	7/16	ENST00000280904.11
DSC2	NM_001406506.1	c.453_454insA	p.Phe152IlefsTer23	frameshift_variant	7/16
DSC2	NM_001406507.1	c.453_454insA	p.Phe152IlefsTer23	frameshift_variant	7/17
DSC2	NM_004949.5	c.882_883insA	p.Phe295IlefsTer23	frameshift_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.882_883insA	p.Phe295IlefsTer23	frameshift_variant	7/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.882_883insA	p.Phe295IlefsTer23	frameshift_variant	7/17	1
DSC2	ENST00000648081.1	c.453_454insA	p.Phe152IlefsTer23	frameshift_variant	8/17
DSC2	ENST00000682357.1	c.453_454insA	p.Phe152IlefsTer23	frameshift_variant	7/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 26, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This sequence change inserts 1 nucleotide in exon 7 of the DSC2 mRNA (c.882dupA), causing a frameshift at codon 295. This creates a premature translational stop signal (p.Phe295Ilefs*23) and is expected to result in an absent or disrupted protein product. -

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: rs1060502989; hg19: chr18-28666598;