18-31086625-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024422.6(DSC2):​c.893A>T​(p.His298Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H298N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

DSC2
NM_024422.6 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.07
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DSC2NM_024422.6 linkuse as main transcriptc.893A>T p.His298Leu missense_variant 7/16 ENST00000280904.11
DSC2NM_004949.5 linkuse as main transcriptc.893A>T p.His298Leu missense_variant 7/17
DSC2NM_001406506.1 linkuse as main transcriptc.464A>T p.His155Leu missense_variant 7/16
DSC2NM_001406507.1 linkuse as main transcriptc.464A>T p.His155Leu missense_variant 7/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DSC2ENST00000280904.11 linkuse as main transcriptc.893A>T p.His298Leu missense_variant 7/161 NM_024422.6 P1Q02487-1
DSC2ENST00000251081.8 linkuse as main transcriptc.893A>T p.His298Leu missense_variant 7/171 Q02487-2
DSC2ENST00000648081.1 linkuse as main transcriptc.464A>T p.His155Leu missense_variant 8/17
DSC2ENST00000682357.1 linkuse as main transcriptc.464A>T p.His155Leu missense_variant 7/16

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 30, 2012The His298Leu variant in DSC2 has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Histidine (His) at position 298 is not wel l conserved in evolution, suggesting that a change to this position may be toler ated. However, additional information is needed to fully assess the clinical sig nificance of the His298Leu variant. -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 10, 2023This missense variant replaces histidine with leucine at codon 298 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 DSC2-related disorders in the literature. This variant has not been identified 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
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJul 19, 2023This missense variant replaces histidine with leucine at codon 298 of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Uncertain
0.068
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.33
T;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.88
D;D;D
MetaSVM
Uncertain
0.0012
D
MutationAssessor
Uncertain
2.7
M;M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-8.8
D;D;.
REVEL
Uncertain
0.53
Sift
Uncertain
0.0010
D;D;.
Sift4G
Uncertain
0.0020
D;D;.
Polyphen
0.98
D;D;.
Vest4
0.67
MVP
0.90
MPC
0.36
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.67
gMVP
0.50

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs397517407; hg19: chr18-28666588; API