18-31546667-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001943.5(DSG2):c.3281G>T(p.Gly1094Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1094D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.248

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018709004).
• BP6: Variant 18-31546667-G-T is Benign according to our data. Variant chr18-31546667-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1729748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.3281G>T	p.Gly1094Val	missense_variant	15/15	ENST00000261590.13
DSG2-AS1	NR_045216.1	n.1346-761C>A		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1	c.2747G>T	p.Gly916Val	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.3281G>T	p.Gly1094Val	missense_variant	15/15	1	NM_001943.5	P1
DSG2-AS1	ENST00000583706.5	n.1384-761C>A		intron_variant, non_coding_transcript_variant		5
DSG2-AS1	ENST00000657343.1	n.697-761C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000602 AC: 15 AN: 249220 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135180

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.0000290

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74460

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000149 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.000755 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000827 AC: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	16
Dann	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.071
Sift	Benign	0.21	T
Sift4G	Uncertain	0.026	D
Polyphen		0.48	P
Vest4		0.096
MVP		0.73
MPC		0.12
ClinPred		0.019	T
GERP RS		2.4
Varity_R		0.024
gMVP		0.45

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: rs144313973; hg19: chr18-29126630;