rs397514038

Positions:

• chr18-31541191-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_001943.5(DSG2):​c.1880-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000479 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DSG2 NM_001943.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 6.33

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 18-31541191-A-G is Pathogenic according to our data. Variant chr18-31541191-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16817.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1}. Variant chr18-31541191-A-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.1880-2A>G		splice_acceptor_variant, intron_variant		ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.1346-2A>G		splice_acceptor_variant, intron_variant			XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.1880-2A>G		splice_acceptor_variant, intron_variant		1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727204

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: 0.00000630

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:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 07, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 12, 2018	This sequence change affects an acceptor splice site in intron 12 of the DSG2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in heterozygosis in an individual affected with right ventricular cardiomyopathy and in compound heterozygosis (in trans) with rare missense varaint in two siblings affected with ARVC (PMID: 16505173, 27532257). This variant is also known as c.1881-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 16817). Experimental studies have shown that this intronic change leads to the inactivation of the natural intron 12 donor splice site and to the activation of a cryptic splice site in exon 13 that results in a transcript susceptible to NMD (PMID: 16505173). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2020	Identified in association with ARVC (Pilichou et al., 2006; Walsh et al., 2017); variant reported as c.1881-2 A>G (due to alternate nomenclature) in an affected patient and her sister who both also harbored a missense variant in the DSG2 gene (Pilichou et al 2006); Published functional studies demonstrate that this variant leads to the inactivation of the natural intron 12 splice acceptor site and the activation of a cryptic splice acceptor site in exon 13, resulting in abnormal gene splicing (Pilichou et al., 2006); Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as either pathogenic or likely pathogenic (ClinVar Variant ID# 16817; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16505173, 23381804, 25525159, 27532257, 31402444, 32686758) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DSG2: PVS1, PM2, PS4:Moderate -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This variant causes an A>G nucleotide substitution at the -2 position of intron 12 of the DSG2 protein. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 38 nucleotides downstream of the native intron 12 splice site. A functional RNA study has shown that this cryptic splice acceptor site is used, leading to a deletion of 38 nucleotides (PMID: 16505173). As a result, this variant is expected to create a frameshift and premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 24704780, 26138720, 27532257). Some of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: PMID: 24704780). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2010	The 1880-2A>G variant has been reported in two siblings with ARVC and was absent from 560 matched control chromosomes, supporting a pathogenic role. However, b oth siblings also carried a second, possibly disease causing variant on the othe r copy of the DSG2 gene (Pilichou, 2006). RNA studies demonstrated that the 1880 -2A>G abolishes the splice site, leading to the use of a cryptic splice site 38 bp downstream. The aberrantly spliced mRNA was shown to lack the first 38 bp of exon 13, which is predicted to cause a frameshift starting at position 627 and p remature termination 19 amino acids later, leading to a truncated or absent prot ein (Pilichou, 2006). In summary, the severity of the change as well as absence from controls suggest that this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 40
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397514038; hg19: chr18-29121154;