chr18-31074850-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_024422.6(DSC2):​c.1721G>A​(p.Ser574Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 0.421

Publications

5 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.36196738).
BP6
Variant 18-31074850-C-T is Benign according to our data. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018. Variant chr18-31074850-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178018.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSC2NM_024422.6 linkc.1721G>A p.Ser574Asn missense_variant Exon 12 of 16 ENST00000280904.11 NP_077740.1 Q02487-1
DSC2NM_004949.5 linkc.1721G>A p.Ser574Asn missense_variant Exon 12 of 17 NP_004940.1 Q02487-2
DSC2NM_001406506.1 linkc.1292G>A p.Ser431Asn missense_variant Exon 12 of 16 NP_001393435.1
DSC2NM_001406507.1 linkc.1292G>A p.Ser431Asn missense_variant Exon 12 of 17 NP_001393436.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSC2ENST00000280904.11 linkc.1721G>A p.Ser574Asn missense_variant Exon 12 of 16 1 NM_024422.6 ENSP00000280904.6 Q02487-1

Frequencies

GnomAD3 genomes
AF:
0.0000921
AC:
14
AN:
152048
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000637
AC:
16
AN:
251034
AF XY:
0.0000369
show subpopulations
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:
0.000141
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000869
AC:
127
AN:
1461758
Hom.:
0
Cov.:
32
AF XY:
0.0000743
AC XY:
54
AN XY:
727164
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39672
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.000110
AC:
122
AN:
1111966
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.467
Heterozygous variant carriers
0
9
18
28
37
46
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000921
AC:
14
AN:
152048
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74260
show subpopulations
African (AFR)
AF:
0.0000725
AC:
3
AN:
41390
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000162
AC:
11
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.457
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000147
Hom.:
0
Bravo
AF:
0.000125
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jul 24, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The DSC2 c.1721G>A; p.Ser574Asn variant (rs150318400) is reported in the literature in an individual affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) and in the parent of a child with sudden unexpected death and suspected ARVC (Quarta 2011, van der Werf 2010). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (16/128894 alleles) in the Genome Aggregation Database. The serine at codon 574 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ser574Asn variant is uncertain at this time. References: Quarta et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123(23):2701-2709. van der Werf C et al. Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands. Heart Rhythm. 2010;7(10):1383-1389. -

May 28, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported in association with ARVC and DCM and in a woman with "probable" ARVC whose child was a victim of sudden unexplained death (PMID: 21606390, 30847666, 32880476, 20646679); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 20646679, 31402444, 30847666, 32880476, 21606390, 38689299, 37937776) -

not specified Uncertain:1Benign:1
Nov 29, 2024
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.1721G>A (p.Ser574Asn) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded 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 6.4e-05 in 251034 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05). c.1721G>A has been reported in the literature in individuals affected with DSC2-related conditions (examples: van der Werf_2010, van Lint_2019, Verdonschot_2020) . These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported (KCNQ1 c.1781G>A, p.R594Q), providing supporting evidence for a benign role (Internal sample). The following publications have been ascertained in the context of this evaluation (PMID: 21606390, 23299917, 20646679, 30847666, 31402444, 32880476, 38689299).ClinVar contains an entry for this variant (Variation ID: 178018). Based on the evidence outlined above, the variant was classified as likely benign. -

May 01, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Ser574Asn variant in DSC2 has been reported in 1 individual with ARVC (Quart a 2011). It has also been identified in 4/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1 50318400). Serine (Ser) at position 574 is not conserved evolution, raising the possibility that a change at this position may be tolerated. In summary, the cli nical significance of the Ser574Asn variant is uncertain. -

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 574 of the DSC2 protein (p.Ser574Asn). This variant is present in population databases (rs150318400, gnomAD 0.01%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular dyplasia/cardiomyopathy, dilated cardiomyopathy, and/or unspecified cardiomyopathy (PMID: 20646679, 21606390, 30847666, 32880476, 37937776). ClinVar contains an entry for this variant (Variation ID: 178018). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
Jan 25, 2024
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 asparagine at codon 574 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 been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390), dilated cardiomyopathy, and unspecified cardiomyopathy (PMID: 30847666, 32880476, 37198425). This variant has also been identified in 17/282410 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. -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Dec 15, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with asparagine at codon 574 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 been reported in an individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). This variant has also been identified in 17/282410 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. -

Cardiovascular phenotype Benign:1
Jun 11, 2021
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
9.1
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T;.;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.17
N
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.36
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.70
N;N;.
PhyloP100
0.42
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.0
N;N;.
REVEL
Benign
0.13
Sift
Benign
0.30
T;T;.
Sift4G
Benign
0.31
T;T;.
Polyphen
0.017
B;B;.
Vest4
0.14
MVP
0.70
MPC
0.076
ClinPred
0.065
T
GERP RS
4.5
Varity_R
0.14
gMVP
0.75
Mutation Taster
=88/12
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

Publications

Other links and lift over

dbSNP: rs150318400; hg19: chr18-28654816; API