18-31092151-C-T

Variant names:

• chr18-31092151-C-T
• rs144799937
• NM_024422.6:c.304G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024422.6(DSC2):​c.304G>A​(p.Glu102Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,078 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:15
• Conservation: PhyloP100: 0.844
• Publications: 20 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01640156).
• BP6: Variant 18-31092151-C-T is Benign according to our data. Variant chr18-31092151-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46189.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00075 (114/152050) while in subpopulation NFE AF = 0.00134 (91/68026). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.304G>A	p.Glu102Lys	missense_variant	Exon 3 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.304G>A	p.Glu102Lys	missense_variant	Exon 3 of 17		NP_004940.1
DSC2	NM_001406506.1	c.-126G>A		5_prime_UTR_variant	Exon 3 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.-126G>A		5_prime_UTR_variant	Exon 3 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.304G>A	p.Glu102Lys	missense_variant	Exon 3 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 114 AN: 152050 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000777 AC: 195 AN: 250872 AF XY: 0.000708

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.00128 AC: 1867 AN: 1461028 Hom.: 3 Cov.: 31 AF XY: 0.00128 AC XY: 930 AN XY: 726780

African (AFR) AF: 0.000179 AC: 6 AN: 33440

American (AMR) AF: 0.000134 AC: 6 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86192

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53400

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5736

European-Non Finnish (NFE) AF: 0.00149 AC: 1658 AN: 1111506

Other (OTH) AF: 0.00124 AC: 75 AN: 60352

GnomAD4 genome AF: 0.000750 AC: 114 AN: 152050 Hom.: 0 Cov.: 33 AF XY: 0.000835 AC XY: 62 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.000393 AC: 6 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68026

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.00130 Hom.: 2

Bravo AF: 0.000748

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000741 AC: 90

EpiCase AF: 0.000872

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Sep 21, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu102Lys variant in DSC2 is classified as likely benign because it has been identified in 0.1% (164/128778) of European chromosomes and 0.2% (22/10356) of Ashkenazi Jewish chromosomes by gnomAD (http://exac.broadinstitute.org), which is higher than the maximal expected allele frequency for a pathogenic variant in DSC2. Glutamic acid (Glu) at position 102 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a lysine (Lys) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools also suggest that the p.Glu102Lys variant may not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -

Oct 08, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DSC2 c.304G>A (p.Glu102Lys) results in a conservative amino acid change located in the Cadherin prodomain (IPR014868) of the enoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251372 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European and 0.0022in the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European and Ashkenazi Jewish control individuals in the gnomAD database is approximately 8- and 13- fold higher (respectively) than the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD) phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism. Though the variant, c.304G>A, has been reported in the literature in individuals affected with ARVD (Beffagna_2007, Quarta_2011, Anastasakis_2012), it has also been detected in unaffected family members (Beffagna_2007, Anastasakis_2012). The variant has also been detected in individuals affected with other cardiomyopathies (hypertrophic cardiomyopathy; Lopes_2012 and left-ventricular non-compaction; Miszalski-Jamka_2017), as well as healthy control populations (Andereasen_2013, Amendola_2015, Hall_2018). One publication reported experimental evidence evaluating an impact on protein function, and indicated that the variant may disrupt localization of the protein to the plasma membrane, however, this study does not allow convincing conclusions about the variant effect (Beffagna_2007). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (6 laboratories cited the variant as likely benign, while 3 cited the variant as VUS). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 27, 2015

Blueprint Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the variant has been observed in disparate phenotypes and is present with an MAF >0.1% in samples unselected for ARVC, we consider this variant a variant of uncertain significance. The variant has been reported in the literature in at least 5 individuals with ARVC (Beffagna 2007, De Bertoli et al 2010, Quarta 2011, Anastasakis 2012). Per the LMM ClinVar submission: "In vitro functional studies suggest that the p.Glu102Lys variant may disrupt proper localization of the protein (Beffagna 2007). However, these types of assays may not accurately represent biological function. Glutamic acid (Glu) at position 102 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a Lysine (Lys) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools also suggest that the p.Glu102Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity." The variant was reported online in 89 of 60,526 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 22nd, 2015). Specifically, the highest frequency was in Europeans with 71/33283 (MAF 0.11%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1 Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:4

Oct 21, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21606390, 23299917, 25637381, 25569433, 17963498, 26310507, 20197793, 23147450, 23396983, 27301361, 28798025, 29802319, 31568572, 31402444) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DSC2: BP4, BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1 Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_mod;PS3_supp;BS1;BP5 -

Sep 19, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiomyopathy Benign:2

Aug 06, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely Benign based on current evidence: This missense variant is located in the N-terminal propeptide sequence of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has shown that this variant may cause the protein to localize to the cytoplasm in addition to the cell-cell junction (PMID: 17963498). However, biological significance of this finding is unknown. This variant has been reported in individuals with arrhythmogenic, dilated and hypertrophic cardiomyopathy (PMID: 17963498, 20197793, 21606390, 23147450, 23396983) but has also been detected in unaffected family members (PMID: 17963498, 23147450). This variant is common in the general population and has been identified in 156/126324 non-Finnish European chromosomes (0.12%) and 21/10134 Ashkenazi Jewish chromosomes (0.21%) by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on collective evidence, this variant is classified as Likely Benign. -

Oct 31, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Found in 2 unrelated patients having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

DSC2-related disorder Benign:1

Mar 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial isolated arrhythmogenic right ventricular dysplasia Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
PhyloP100		0.84
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.28
Sift	Benign	0.42	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.016	B;B
Vest4		0.73
MVP		0.66
MPC		0.096
ClinPred		0.010	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.099
gMVP		0.32
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144799937; hg19: chr18-28672114;