rs755276378

Variant names:

• chr18-31068972-C-A
• rs755276378
• NM_024422.6:c.2430G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-31068972-C-A
• chr18-31068972-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024422.6(DSC2):​c.2430G>T​(p.Arg810Ser) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R810R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.230
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2808512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2430G>T	p.Arg810Ser	missense_variant	Exon 15 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2430G>T	p.Arg810Ser	missense_variant	Exon 15 of 17		NP_004940.1
DSC2	NM_001406506.1	c.2001G>T	p.Arg667Ser	missense_variant	Exon 15 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.2001G>T	p.Arg667Ser	missense_variant	Exon 15 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2430G>T	p.Arg810Ser	missense_variant	Exon 15 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T;.;.
Eigen	Benign	0.091
Eigen_PC	Benign	-0.0021
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.1	M;M;.
PhyloP100		0.23
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	D;D;.
REVEL	Benign	0.22
Sift	Benign	0.052	T;D;.
Sift4G	Uncertain	0.052	T;D;.
Polyphen		0.93	P;P;.
Vest4		0.50
MutPred		0.40		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);.;
MVP		0.82
MPC		0.38
ClinPred		0.83	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.53
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs755276378; hg19: chr18-28648938;