chr18-31071603-AC-A

Position:

• chr18-31071603-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_024422.6(DSC2):​c.2125+1delG variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000205 in 1,460,652 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSC2 NM_024422.6 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 4.30

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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0872136 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of 44, new splice context is: aaaGTaact. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31071603-AC-A is Pathogenic according to our data. Variant chr18-31071603-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31071603-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2125+1delG		splice_donor_variant, intron_variant		ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2125+1delG		splice_donor_variant, intron_variant			NP_004940.1
DSC2	NM_001406506.1	c.1696+1delG		splice_donor_variant, intron_variant			NP_001393435.1
DSC2	NM_001406507.1	c.1696+1delG		splice_donor_variant, intron_variant			NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2125+1delG		splice_donor_variant, intron_variant		1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2125+1delG		splice_donor_variant, intron_variant		1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1696+1delG		splice_donor_variant, intron_variant				ENSP00000497441.1
DSC2	ENST00000682357.1	c.1696+1delG		splice_donor_variant, intron_variant				ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460652 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726756

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.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 18, 2017	This c.2125+1del variant has been reported in dbSNP (rs794728072) and ClinVar (RCV000181172.1). The frequency of this variant is unknown and this variant has not previously been observed in our patient cohort. This c.2125+1del variant affects the invariant acceptor splice site of intron 13 of the DSC2 gene. While not validated for clinical use, the computer-based algorithms predict this variant to disrupt the invariant donor splicing site. Loss of function variants including splicing site variants are disease-causing for this disorder. It is thus interpreted as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2023	This sequence change affects a splice site in intron 13 of the DSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy and/or ventricular tachycardia (PMID: 28153106, 31931689, 33662488). ClinVar contains an entry for this variant (Variation ID: 199778). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 16, 2021	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2025	While this variant has been reported in studies exploring ARVC, these individuals either did not manifest symptoms of disease or it is unclear whether the individual(s) harboring this variant were clinically diagnosed with ARVC (PMID: 31638835, 28153106); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon 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: 31447099, 28153106, 33662488, 31638835, 31931689) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dilated cardiomyopathy 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Mar 14, 2019

- -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 21, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The c.2125+1del G variant in DSC2 has been reported in 1 individual with ARVC (Venlet 2017) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 199778). The c.2125+1delG variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alt ered splicing leading to an abnormal or absent protein. Splice site and other lo ss of function variants in DSC2 have been reported in individuals with ARVC. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of the c.2152+1delG variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 46
DS_DL_spliceai		0.96		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: rs794728072; hg19: chr18-28651569;