18-31079958-C-G

Variant names:

Variant summary

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

The NM_024422.6(DSC2):c.1552G>C(p.Val518Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,854 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 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -1.01

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 links:

Genome browser will be placed here

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=0.014665872).

BP6

Variant 18-31079958-C-G is Benign according to our data. Variant chr18-31079958-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46169.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000394 (6/152234) while in subpopulation AMR AF= 0.000392 (6/15288). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 2 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
DSC2	NM_024422.6 link	c.1552G>C	p.Val518Leu	missense_variant	Exon 11 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 link	c.1552G>C	p.Val518Leu	missense_variant	Exon 11 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 link	c.1123G>C	p.Val375Leu	missense_variant	Exon 11 of 16		NP_001393435.1
DSC2	NM_001406507.1 link	c.1123G>C	p.Val375Leu	missense_variant	Exon 11 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSC2	ENST00000280904.11 link	c.1552G>C	p.Val518Leu	missense_variant	Exon 11 of 16	1	NM_024422.6	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081.8 link	c.1552G>C	p.Val518Leu	missense_variant	Exon 11 of 17	1		ENSP00000251081.6	Q02487-2
DSC2	ENST00000648081.1 link	c.1123G>C	p.Val375Leu	missense_variant	Exon 12 of 17			ENSP00000497441.1	A0A3B3ISU0
DSC2	ENST00000682357.1 link	c.1123G>C	p.Val375Leu	missense_variant	Exon 11 of 16			ENSP00000507826.1	A0A3B3ISU0

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000267

AC:

AN:

251108

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00194

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:

0.0000540

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00177

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:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

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

Bravo

AF:

0.0000680

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jul 01, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thep.Val518Leu variant in DSC2 is classified as likely benign because it has been identified in 0.14% (85/60010) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -

Arrhythmogenic right ventricular dysplasia 11

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Jun 27, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 21, 2019

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

0.32

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.073

T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.86

L;L;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.96

N;N;.

REVEL

Benign

0.094

Sift

Benign

0.19

T;T;.

Sift4G

Benign

0.074

T;T;.

Polyphen

0.74

P;P;.

Vest4

0.18

MutPred

0.57

Gain of catalytic residue at V518 (P = 0.1202);Gain of catalytic residue at V518 (P = 0.1202);.;

MVP

0.50

MPC

0.22

ClinPred

0.12

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over