18-31068130-G-C

Variant names:

• chr18-31068130-G-C
• NM_024422.6:c.2591C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_024422.6(DSC2):​c.2591C>G​(p.Ser864Trp) variant causes a missense change. 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: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64

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.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity DSC2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2591C>G	p.Ser864Trp	missense_variant	Exon 16 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_001406506.1	c.2162C>G	p.Ser721Trp	missense_variant	Exon 16 of 16		NP_001393435.1
DSC2	NM_004949.5	c.*93C>G		3_prime_UTR_variant	Exon 17 of 17		NP_004940.1
DSC2	NM_001406507.1	c.*93C>G		3_prime_UTR_variant	Exon 17 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2591C>G	p.Ser864Trp	missense_variant	Exon 16 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081	c.*93C>G		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.2162C>G	p.Ser721Trp	missense_variant	Exon 17 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.2162C>G	p.Ser721Trp	missense_variant	Exon 16 of 16			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

Cardiovascular phenotype Uncertain:1

Nov 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S864W variant (also known as c.2591C>G), located in coding exon 16 of the DSC2 gene, results from a C to G substitution at nucleotide position 2591. The serine at codon 864 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.73		Loss of disorder (P = 0.0073);.;
MVP		0.97
MPC		0.50
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28648096;