18-31082933-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_024422.6(DSC2):​c.1070G>A​(p.Arg357His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.442
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 -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.003782928).
BP6
Variant 18-31082933-C-T is Benign according to our data. Variant chr18-31082933-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191622.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=4}. Variant chr18-31082933-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152266) while in subpopulation EAS AF= 0.00308 (16/5188). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSC2NM_024422.6 linkc.1070G>A p.Arg357His missense_variant Exon 8 of 16 ENST00000280904.11 NP_077740.1 Q02487-1
DSC2NM_004949.5 linkc.1070G>A p.Arg357His missense_variant Exon 8 of 17 NP_004940.1 Q02487-2
DSC2NM_001406506.1 linkc.641G>A p.Arg214His missense_variant Exon 8 of 16 NP_001393435.1
DSC2NM_001406507.1 linkc.641G>A p.Arg214His missense_variant Exon 8 of 17 NP_001393436.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSC2ENST00000280904.11 linkc.1070G>A p.Arg357His missense_variant Exon 8 of 16 1 NM_024422.6 ENSP00000280904.6 Q02487-1
DSC2ENST00000251081.8 linkc.1070G>A p.Arg357His missense_variant Exon 8 of 17 1 ENSP00000251081.6 Q02487-2
DSC2ENST00000648081.1 linkc.641G>A p.Arg214His missense_variant Exon 9 of 17 ENSP00000497441.1 A0A3B3ISU0
DSC2ENST00000682357.1 linkc.641G>A p.Arg214His missense_variant Exon 8 of 16 ENSP00000507826.1 A0A3B3ISU0

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152150
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00308
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:
0.000231
AC:
58
AN:
250972
Hom.:
0
AF XY:
0.000177
AC XY:
24
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000261
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00267
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:
0.0000582
AC:
85
AN:
1460888
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
726788
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00136
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.0000995
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152266
Hom.:
0
Cov.:
33
AF XY:
0.000282
AC XY:
21
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00308
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000660
Hom.:
0
Bravo
AF:
0.000246
ExAC
AF:
0.000165
AC:
20
Asia WGS
AF:
0.000289
AC:
2
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 15, 2018This 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. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 12, 2021Variant summary: DSC2 c.1070G>A (p.Arg357His) results in a non-conservative amino acid change located in the third cadherin-like repeat (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 282370 control chromosomes, predominantly at a frequency of 0.0027 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 100-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.1070G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, three classifying the variant as likely benign, and one calling it a VUS. Based on the evidence outlined above, the variant was classified as benign. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Arrhythmogenic right ventricular dysplasia 11 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2025- -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 13, 2018- -
DSC2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 05, 2022This 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
Benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 04, 2021This alteration is classified as 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. -
Familial isolated arrhythmogenic right ventricular dysplasia Benign:1
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 23, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
16
DANN
Benign
0.97
DEOGEN2
Benign
0.086
T;.;.
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.77
T;T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.0038
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.91
L;L;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.6
N;N;.
REVEL
Benign
0.038
Sift
Benign
0.11
T;T;.
Sift4G
Benign
0.12
T;D;.
Polyphen
0.0050
B;B;.
Vest4
0.16
MutPred
0.43
Loss of solvent accessibility (P = 0.0468);Loss of solvent accessibility (P = 0.0468);.;
MVP
0.54
MPC
0.095
ClinPred
0.021
T
GERP RS
1.5
Varity_R
0.11
gMVP
0.51

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: rs201201194; hg19: chr18-28662899; COSMIC: COSV51870912; API