rs999869714

Positions:

• chr18-31082946-G-C
• chr18-31082946-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024422.6(DSC2):​c.1057C>G​(p.Pro353Ala) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.22

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1057C>G	p.Pro353Ala	missense_variant	8/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1057C>G	p.Pro353Ala	missense_variant	8/17		NP_004940.1
DSC2	NM_001406506.1	c.628C>G	p.Pro210Ala	missense_variant	8/16		NP_001393435.1
DSC2	NM_001406507.1	c.628C>G	p.Pro210Ala	missense_variant	8/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1057C>G	p.Pro353Ala	missense_variant	8/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1057C>G	p.Pro353Ala	missense_variant	8/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.628C>G	p.Pro210Ala	missense_variant	9/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.628C>G	p.Pro210Ala	missense_variant	8/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the extracellular cadherin domain 2 of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.5	H;H;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.2	D;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.014	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.86
MutPred		0.89		Loss of phosphorylation at T354 (P = 0.1384);Loss of phosphorylation at T354 (P = 0.1384);.;
MVP		0.98
MPC		0.42
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs999869714; hg19: chr18-28662912;