18-31071823-G-C

Variant names:

• chr18-31071823-G-C
• rs764355417
• NM_024422.6:c.1907C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_024422.6(DSC2):​c.1907C>G​(p.Ser636Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. S636A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.322
• Publications: 0 publications found

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]

DSC2 Gene-Disease associations (from GenCC):

• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30291975).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	NM_024422.6	MANE Select	c.1907C>G	p.Ser636Cys	missense	Exon 13 of 16	NP_077740.1
	DSC2	NM_004949.5		c.1907C>G	p.Ser636Cys	missense	Exon 13 of 17	NP_004940.1
	DSC2	NM_001406506.1		c.1478C>G	p.Ser493Cys	missense	Exon 13 of 16	NP_001393435.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.1907C>G	p.Ser636Cys	missense	Exon 13 of 16	ENSP00000280904.6
	DSC2	ENST00000251081.8	TSL:1	c.1907C>G	p.Ser636Cys	missense	Exon 13 of 17	ENSP00000251081.6
	DSC2	ENST00000713707.1		c.1907C>G	p.Ser636Cys	missense	Exon 13 of 16	ENSP00000519010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250424 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461208 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111552

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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

May 08, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 630583). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is present in population databases (rs764355417, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 636 of the DSC2 protein (p.Ser636Cys).

Cardiomyopathy Uncertain:1

Jan 20, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with cysteine at codon 636 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 3/250424 chromosomes 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

Mar 12, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Has not been previously published as pathogenic or benign to our knowledge

Cardiovascular phenotype Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1907C>G (p.S636C) alteration is located in exon 13 (coding exon 13) of the DSC2 gene. This alteration results from a C to G substitution at nucleotide position 1907, causing the serine (S) at amino acid position 636 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.072
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-0.32
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Uncertain	0.011	D
Sift4G	Benign	0.069	T
Polyphen		0.98	D
Vest4		0.41
MutPred		0.53		Loss of disorder (P = 0.0294)
MVP		0.69
MPC		0.32
ClinPred		0.64	D
GERP RS		0.62
Varity_R		0.26
gMVP		0.57
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs764355417; hg19: chr18-28651789; COSMIC: COSV51866496;