18-31498295-T-C

Position:

• chr18-31498295-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000261590.13(DSG2):​c.44T>C​(p.Leu15Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000018 in 1,111,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. L15Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: DSG2 ENST00000261590.13 missense, splice_region
• Scores: Splicing: ADA: 0.007507
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.44T>C	p.Leu15Pro	missense_variant, splice_region_variant	1/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-529T>C		splice_region_variant, 5_prime_UTR_variant	1/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.44T>C	p.Leu15Pro	missense_variant, splice_region_variant	1/15	1	NM_001943.5	ENSP00000261590	P1
DSG2	ENST00000683654.1	c.44T>C	p.Leu15Pro	missense_variant, splice_region_variant	1/7			ENSP00000506971
DSG2	ENST00000682241.2	c.44T>C	p.Leu15Pro	missense_variant, splice_region_variant	1/7			ENSP00000507600
DSG2	ENST00000585206.1	c.44T>C	p.Leu15Pro	missense_variant, splice_region_variant	1/6	2		ENSP00000462503

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000180 AC: 2 AN: 1111686 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 528156

Gnomad4 AFR exome AF: 0.0000425

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: 0.00000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Benign	0.70
DEOGEN2	Uncertain	0.57	D;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.36	T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.22
Sift	Uncertain	0.023	D;.
Sift4G	Uncertain	0.016	D;T
Polyphen		0.21	B;.
Vest4		0.53
MutPred		0.66		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.57
MPC		0.13
ClinPred		0.30	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0075
dbscSNV1_RF	Benign	0.082
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: rs372174546; hg19: chr18-29078258;