rs764925318

Positions:

• chr18-31546283-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001943.5(DSG2):​c.2897G>C​(p.Arg966Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,449,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.94

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.2897G>C	p.Arg966Thr	missense_variant	15/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1	n.1346-377C>G		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1	c.2363G>C	p.Arg788Thr	missense_variant	16/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.2897G>C	p.Arg966Thr	missense_variant	15/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5	n.1384-377C>G		intron_variant, non_coding_transcript_variant		5
DSG2-AS1	ENST00000657343.1	n.697-377C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000456 AC: 11 AN: 240998 Hom.: 0 AF XY: 0.0000230 AC XY: 3 AN XY: 130298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000266

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: 0.000344

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1449976 Hom.: 0 Cov.: 32 AF XY: 0.00000834 AC XY: 6 AN XY: 719714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000318

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2022	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 966 of the DSG2 protein (p.Arg966Thr). This variant is present in population databases (rs764925318, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 326488). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces arginine with threonine at codon 966 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has been identified in 11/240998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.63
Sift	Benign	0.30	T
Sift4G	Benign	0.072	T
Polyphen		0.91	P
Vest4		0.51
MutPred		0.66		Gain of glycosylation at R966 (P = 0.0401);
MVP		0.91
MPC		0.42
ClinPred		0.59	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs764925318; hg19: chr18-29126246;