rs201201194

Variant names:

• chr18-31082933-C-A
• rs201201194
• NM_024422.6:c.1070G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-31082933-C-A
• chr18-31082933-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.1070G>T​(p.Arg357Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. R357H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.442
• Publications: 0 publications found

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

ACMG classification

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=0.2196545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1070G>T	p.Arg357Leu	missense_variant	Exon 8 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1070G>T	p.Arg357Leu	missense_variant	Exon 8 of 17		NP_004940.1
DSC2	NM_001406506.1	c.641G>T	p.Arg214Leu	missense_variant	Exon 8 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.641G>T	p.Arg214Leu	missense_variant	Exon 8 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1070G>T	p.Arg357Leu	missense_variant	Exon 8 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460888 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726788

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jul 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R357L variant (also known as c.1070G>T), located in coding exon 8 of the DSC2 gene, results from a G to T substitution at nucleotide position 1070. The arginine at codon 357 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		0.44
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Benign	0.059
Sift	Uncertain	0.010	D;D;.
Sift4G	Uncertain	0.029	D;D;.
Polyphen		0.65	P;P;.
Vest4		0.40
MutPred		0.48		Loss of catalytic residue at R357 (P = 0.0055);Loss of catalytic residue at R357 (P = 0.0055);.;
MVP		0.68
MPC		0.28
ClinPred		0.95	D
GERP RS		1.5
Varity_R		0.47
gMVP		0.65
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs201201194; hg19: chr18-28662899;