18-31069033-C-T

Variant names:

• chr18-31069033-C-T
• rs1555637241
• NM_024422.6:c.2369G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024422.6(DSC2):​c.2369G>A​(p.Gly790Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G790R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.93

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 Uncertain_significance. Variant got 2 ACMG points.

• 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.2369G>A	p.Gly790Glu	missense_variant	Exon 15 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2369G>A	p.Gly790Glu	missense_variant	Exon 15 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1940G>A	p.Gly647Glu	missense_variant	Exon 15 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1940G>A	p.Gly647Glu	missense_variant	Exon 15 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2369G>A	p.Gly790Glu	missense_variant	Exon 15 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2369G>A	p.Gly790Glu	missense_variant	Exon 15 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1940G>A	p.Gly647Glu	missense_variant	Exon 16 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1940G>A	p.Gly647Glu	missense_variant	Exon 15 of 16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460614 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726618

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 790 of the DSC2 protein (p.Gly790Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 432627). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. 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. -

Cardiomyopathy Uncertain:1

Mar 28, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with glutamic acid at codon 790 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -

not provided Uncertain:1

Oct 28, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Cardiovascular phenotype Uncertain:1

Mar 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G790E variant (also known as c.2369G>A), located in coding exon 15 of the DSC2 gene, results from a G to A substitution at nucleotide position 2369. The glycine at codon 790 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.1	M;M;.
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.9	D;D;.
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.014	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.50
MutPred		0.27		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);.;
MVP		0.93
MPC		0.47
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.58

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: rs1555637241; hg19: chr18-28648999; COSMIC: COSV104567562;