chr18-31524792-G-A

Position:

• chr18-31524792-G-A

Variant summary

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

The NM_001943.5(DSG2):​c.918G>A​(p.Trp306Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSG2 NM_001943.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 9.02

Genes affected

DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]

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 18-31524792-G-A is Pathogenic according to our data. Variant chr18-31524792-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16811.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=1}. Variant chr18-31524792-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.918G>A	p.Trp306Ter	stop_gained	8/15	ENST00000261590.13
DSG2	XM_047437315.1	c.384G>A	p.Trp128Ter	stop_gained	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.918G>A	p.Trp306Ter	stop_gained	8/15	1	NM_001943.5	P1
DSG2	ENST00000682087.2	n.749G>A		non_coding_transcript_exon_variant	6/6
DSG2	ENST00000683614.2	n.749G>A		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461838 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 31, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16811). This variant is also known as W305X. This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16773573). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp306*) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 28, 2021	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2023

Variant, reported as c.915G>A (W305X) using alternate nomenclature, was observed in the compound heterozygous state with DSG2 R48H in an individual with ARVC, as well as in the heterozygous state in two unaffected relatives (PMID: 16773573); Observed in an individual with ARVC (PMID: 31386562); Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense 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; This variant is associated with the following publications: (PMID: 20857253, 25525159, 20031617, 31402444, 31386562, 16773573) -

Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 25, 2021

- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

This variant changes 1 nucleotide in exon 8 of the DSG2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (referred to as c.915G>A, W305X) has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried another pathogenic variant in the DSG2 gene that could explain the observed phenotype (PMID: 16773573). This variant has been observed in the proband's unaffected mother and sister as well. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSC2 truncation and splice variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.90
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs121913007; hg19: chr18-29104755;