dbSNP rs145560678: DSC2:p.Val303Leu (chr18-31086611-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024422.6(DSC2):c.907G>C(p.Val303Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V303M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.758

Publications

0 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

DSC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22332847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DSC2	NM_024422.6 link	c.907G>C	p.Val303Leu	missense_variant	Exon 7 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5 link	c.907G>C	p.Val303Leu	missense_variant	Exon 7 of 17		NP_004940.1
DSC2	NM_001406506.1 link	c.478G>C	p.Val160Leu	missense_variant	Exon 7 of 16		NP_001393435.1
DSC2	NM_001406507.1 link	c.478G>C	p.Val160Leu	missense_variant	Exon 7 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 link	c.907G>C	p.Val303Leu	missense_variant	Exon 7 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.98

L;L;.

PhyloP100

0.76

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.4

N;N;.

REVEL

Benign

0.075

Sift

Benign

0.031

D;T;.

Sift4G

Uncertain

0.058

T;T;.

Polyphen

0.61

P;P;.

Vest4

0.30

MutPred

0.47

Gain of disorder (P = 0.1356);Gain of disorder (P = 0.1356);.;

MVP

0.55

MPC

0.14

ClinPred

0.44

GERP RS

3.8

Varity_R

0.25

gMVP

0.45

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over