rs1555637433

Positions:

• chr18-31070723-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_024422.6(DSC2):​c.2250+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 splice_region, intron
• Scores: Splicing: ADA: 0.01139
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.409

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 18-31070723-T-C is Benign according to our data. Variant chr18-31070723-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2250+3A>G		splice_region_variant, intron_variant		ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2250+3A>G		splice_region_variant, intron_variant			NP_004940.1
DSC2	NM_001406506.1	c.1821+3A>G		splice_region_variant, intron_variant			NP_001393435.1
DSC2	NM_001406507.1	c.1821+3A>G		splice_region_variant, intron_variant			NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2250+3A>G		splice_region_variant, intron_variant		1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2250+3A>G		splice_region_variant, intron_variant		1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1821+3A>G		splice_region_variant, intron_variant				ENSP00000497441.1
DSC2	ENST00000682357.1	c.1821+3A>G		splice_region_variant, intron_variant				ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461414 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727000

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2022

This sequence change falls in intron 14 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. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 468378). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.020		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: rs1555637433; hg19: chr18-28650689;