18-31521157-G-C

Position:

• chr18-31521157-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001943.5(DSG2):​c.437G>C​(p.Arg146Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R146H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31521157-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.437G>C	p.Arg146Pro	missense_variant	5/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-98G>C		5_prime_UTR_variant	6/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.437G>C	p.Arg146Pro	missense_variant	5/15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.60
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Benign	0.26
Sift	Benign	0.11	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.24	B;.
Vest4		0.77
MutPred		0.51		Loss of ubiquitination at K141 (P = 0.063);Loss of ubiquitination at K141 (P = 0.063);
MVP		0.76
MPC		0.48
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.64
gMVP		0.92

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: rs113451409; hg19: chr18-29101120;