rs397517389

Variant names:

• chr18-31082924-A-C
• rs397517389
• NM_024422.6:c.1077+2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_024422.6(DSC2):​c.1077+2T>G variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSC2 NM_024422.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.64
• Publications: 1 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):

• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.049889136 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1077+2T>G		splice_donor_variant, intron_variant	Intron 8 of 15	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1077+2T>G		splice_donor_variant, intron_variant	Intron 8 of 16		NP_004940.1
DSC2	NM_001406506.1	c.648+2T>G		splice_donor_variant, intron_variant	Intron 8 of 15		NP_001393435.1
DSC2	NM_001406507.1	c.648+2T>G		splice_donor_variant, intron_variant	Intron 8 of 16		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1077+2T>G		splice_donor_variant, intron_variant	Intron 8 of 15	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Uncertain:1

Jul 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a T to G nucleotide substitution at the +2 position of intron 8 of the DSC2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. 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. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Feb 27, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1077+2T>G variant in DSC2 has been identified in 1 individual with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC; LMM data) and has also been reported by other clinical laboratories in ClinVar (Variation ID 46161). It was absent from large population studies (gnomAD v4.0.0). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. However, exon 8, which is affected by this variant, is in frame and consists of only 135 base pairs and encodes less than 10% of the DSC2 protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting. -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a T to G nucleotide substitution at the +2 position of intron 8 of the DSC2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. 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	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
GERP RS		5.4
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs397517389; hg19: chr18-28662890;