18-31091023-G-C

Variant names:

• chr18-31091023-G-C
• NM_024422.6:c.474+5C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024422.6(DSC2):​c.474+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 splice_region, intron
• Scores: Splicing: ADA: 0.00003107
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00300

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.474+5C>G		splice_region_variant, intron_variant	Intron 4 of 15	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.474+5C>G		splice_region_variant, intron_variant	Intron 4 of 16		NP_004940.1
DSC2	NM_001406506.1	c.45+5C>G		splice_region_variant, intron_variant	Intron 4 of 15		NP_001393435.1
DSC2	NM_001406507.1	c.45+5C>G		splice_region_variant, intron_variant	Intron 4 of 16		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.474+5C>G		splice_region_variant, intron_variant	Intron 4 of 15	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.474+5C>G		splice_region_variant, intron_variant	Intron 4 of 16	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.45+5C>G		splice_region_variant, intron_variant	Intron 5 of 16			ENSP00000497441.1
DSC2	ENST00000682357.1	c.45+5C>G		splice_region_variant, intron_variant	Intron 4 of 15			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

May 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the DSC2 gene. It does not directly change the encoded amino acid sequence of the DSC2 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28670986;