rs201845396

Variant names:

• chr18-31545856-C-A
• rs201845396
• NM_001943.5:c.2470C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31545856-C-A
• chr18-31545856-C-G
• chr18-31545856-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001943.5(DSG2):​c.2470C>A​(p.Arg824Ser) 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. 17/22 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. R824H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.185
• Publications: 0 publications found

Genes affected

DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]

DSG2-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03139776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5	c.2470C>A	p.Arg824Ser	missense_variant	Exon 15 of 15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.1936C>A	p.Arg646Ser	missense_variant	Exon 16 of 16		XP_047293271.1
DSG2-AS1	NR_045216.1	n.1396G>T		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.2470C>A	p.Arg824Ser	missense_variant	Exon 15 of 15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Dec 14, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R824S variant (also known as c.2470C>A), located in coding exon 15 of the DSG2 gene, results from a C to A substitution at nucleotide position 2470. The arginine at codon 824 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. 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	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.5
DANN	Benign	0.79
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.18
PrimateAI	Benign	0.19	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.13
MutPred		0.30		Loss of stability (P = 0.0153);
MVP		0.53
MPC		0.086
ClinPred		0.18	T
GERP RS		-1.8
Varity_R		0.056
gMVP		0.16
Mutation Taster		=71/29	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: rs201845396; hg19: chr18-29125819;