rs34065672

chr18-31546094-C-Achr18-31546094-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001943.5(DSG2):c.2708C>A(p.Thr903Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. T903I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.848

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24525383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.2708C>A	p.Thr903Asn	missense_variant	15/15	ENST00000261590.13
DSG2-AS1	NR_045216.1	n.1346-188G>T		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1	c.2174C>A	p.Thr725Asn	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.2708C>A	p.Thr903Asn	missense_variant	15/15	1	NM_001943.5	P1
DSG2-AS1	ENST00000583706.5	n.1384-188G>T		intron_variant, non_coding_transcript_variant		5
DSG2-AS1	ENST00000657343.1	n.697-188G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.039	D
Polyphen		0.45	P
Vest4		0.23
MutPred		0.18		Loss of sheet (P = 0.0357);
MVP		0.81
MPC		0.15
ClinPred		0.58	D
GERP RS		3.3
Varity_R		0.11
gMVP		0.26

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: rs34065672; hg19: chr18-29126057;