rs143040393

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_024422.6(DSC2):​c.1789G>T​(p.Val597Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

4
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.654
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03174147).
BP6
Variant 18-31074782-C-A is Benign according to our data. Variant chr18-31074782-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 199784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31074782-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000585 (89/152226) while in subpopulation AFR AF= 0.00202 (84/41544). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSC2NM_024422.6 linkc.1789G>T p.Val597Phe missense_variant Exon 12 of 16 ENST00000280904.11 NP_077740.1 Q02487-1
DSC2NM_004949.5 linkc.1789G>T p.Val597Phe missense_variant Exon 12 of 17 NP_004940.1 Q02487-2
DSC2NM_001406506.1 linkc.1360G>T p.Val454Phe missense_variant Exon 12 of 16 NP_001393435.1
DSC2NM_001406507.1 linkc.1360G>T p.Val454Phe 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.1789G>T p.Val597Phe missense_variant Exon 12 of 16 1 NM_024422.6 ENSP00000280904.6 Q02487-1
DSC2ENST00000251081.8 linkc.1789G>T p.Val597Phe missense_variant Exon 12 of 17 1 ENSP00000251081.6 Q02487-2
DSC2ENST00000648081.1 linkc.1360G>T p.Val454Phe missense_variant Exon 13 of 17 ENSP00000497441.1 A0A3B3ISU0
DSC2ENST00000682357.1 linkc.1360G>T p.Val454Phe missense_variant Exon 12 of 16 ENSP00000507826.1 A0A3B3ISU0

Frequencies

GnomAD3 genomes
AF:
0.000579
AC:
88
AN:
152108
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00200
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000155
AC:
39
AN:
251108
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135720
show subpopulations
Gnomad AFR exome
AF:
0.00215
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461788
Hom.:
0
Cov.:
32
AF XY:
0.0000358
AC XY:
26
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00143
Gnomad4 AMR exome
AF:
0.000157
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:
0.00
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000585
AC:
89
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.000470
AC XY:
35
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.00202
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000133
Hom.:
0
Bravo
AF:
0.000695
ESP6500AA
AF:
0.00250
AC:
11
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000181
AC:
22

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteOct 19, 2019- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 31, 2017This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 09, 2024Variant summary: DSC2 c.1789G>T (p.Val597Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251108 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1789G>T has been reported in the literature in individuals affected with sudden cardiac death and was evaluated as a benign variant (Campuzano_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25447171). ClinVar contains an entry for this variant (Variation ID: 199784). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 21, 2024- -
Arrhythmogenic right ventricular dysplasia 11 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2025- -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 07, 2019- -
DSC2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 20, 2023This 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). -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 04, 2019This 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
0.13
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
3.2
DANN
Uncertain
0.98
DEOGEN2
Benign
0.35
T;.;.
Eigen
Benign
-0.96
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.072
N
LIST_S2
Benign
0.71
T;T;T
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.032
T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
1.8
L;L;.
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.3
D;D;.
REVEL
Benign
0.11
Sift
Uncertain
0.0070
D;D;.
Sift4G
Uncertain
0.0060
D;D;.
Polyphen
0.0020
B;B;.
Vest4
0.20
MVP
0.71
MPC
0.098
ClinPred
0.027
T
GERP RS
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.24
gMVP
0.65

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143040393; hg19: chr18-28654748; API