chr18-31093616-TG-T

Variant names:

• chr18-31093616-TG-T
• rs397517408
• NM_024422.6:c.96delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024422.6(DSC2):​c.96delC​(p.Cys32fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DSC2 NM_024422.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 0.550
• Publications: 2 publications found

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]

DSC2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 92 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31093616-TG-T is Pathogenic according to our data. Variant chr18-31093616-TG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46204.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	NM_024422.6	MANE Select	c.96delC	p.Cys32fs	frameshift	Exon 2 of 16	NP_077740.1	Q02487-1
	DSC2	NM_004949.5		c.96delC	p.Cys32fs	frameshift	Exon 2 of 17	NP_004940.1	Q02487-2
	DSC2	NM_001406506.1		c.-334delC		5_prime_UTR	Exon 2 of 16	NP_001393435.1	A0A3B3ISU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.96delC	p.Cys32fs	frameshift	Exon 2 of 16	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.96delC	p.Cys32fs	frameshift	Exon 2 of 17	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.96delC	p.Cys32fs	frameshift	Exon 2 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448060 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720510

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25610

East Asian (EAS) AF: 0.00 AC: 0 AN: 39208

South Asian (SAS) AF: 0.00 AC: 0 AN: 85358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1102814

Other (OTH) AF: 0.00 AC: 0 AN: 59562

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Cardiovascular phenotype (2)
2	-	-	not provided (2)
1	-	-	Arrhythmogenic right ventricular cardiomyopathy (1)
1	-	-	Arrhythmogenic right ventricular dysplasia 11 (1)
1	-	-	Cardiomyopathy (1)
1	-	-	DSC2-related disorder (1)
-	1	-	Familial isolated arrhythmogenic right ventricular dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.55
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397517408; hg19: chr18-28673579;