chr18-31498254-G-C

Variant names:

• chr18-31498254-G-C
• NM_001943.5:c.3G>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_001943.5(DSG2):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000181 in 1,107,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: DSG2 NM_001943.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 534 CDS bases. Genomic position: 31522093. Lost 0.159 part of the original CDS.
• PS1: Another start lost variant in NM_001943.5 (DSG2) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-31498254-G-C is Pathogenic according to our data. Variant chr18-31498254-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-570G>C		5_prime_UTR_variant	Exon 1 of 16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.3G>C	p.Met1?	start_lost	Exon 1 of 15	1	NM_001943.5	ENSP00000261590.8
DSG2	ENST00000683654.1	c.3G>C	p.Met1?	start_lost	Exon 1 of 7			ENSP00000506971.1
DSG2	ENST00000682241.2	c.3G>C	p.Met1?	start_lost	Exon 1 of 7			ENSP00000507600.2
DSG2	ENST00000585206.1	c.3G>C	p.Met1?	start_lost	Exon 1 of 6	2		ENSP00000462503.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000181 AC: 2 AN: 1107296 Hom.: 0 Cov.: 30 AF XY: 0.00000380 AC XY: 2 AN XY: 526458

Gnomad4 AFR exome AF: 0.00

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: 0.00000215

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.55	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.92	P;.
Vest4		0.58
MutPred		0.99		Loss of glycosylation at P5 (P = 0.1075);Loss of glycosylation at P5 (P = 0.1075);
MVP		0.82
ClinPred		0.92	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-29078217;