18-31542836-G-A

Variant names:

• chr18-31542836-G-A
• rs2278792
• NM_001943.5:c.2318G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001943.5(DSG2):​c.2318G>A​(p.Arg773Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,376,676 control chromosomes in the GnomAD database, including 55,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R773G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (4237 hom., cov: 26)
  • Exomes 𝑓: 0.30 (51548 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.83
• Publications: 40 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026043653).
• BP6: Variant 18-31542836-G-A is Benign according to our data. Variant chr18-31542836-G-A is described in ClinVar as Benign. ClinVar VariationId is 44300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001943.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.2318G>A	p.Arg773Lys	missense	Exon 14 of 15	NP_001934.2	Q14126
	DSG2-AS1	NR_045216.1		n.1810+266C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.2318G>A	p.Arg773Lys	missense	Exon 14 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.2309G>A	p.Arg770Lys	missense	Exon 15 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.2309G>A	p.Arg770Lys	missense	Exon 16 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.230 AC: 32204 AN: 140046 Hom.: 4233 Cov.: 26

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.265 AC: 53755 AN: 202736 AF XY: 0.264

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.467

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.299 AC: 369845 AN: 1236560 Hom.: 51548 Cov.: 35 AF XY: 0.298 AC XY: 181338 AN XY: 608972

African (AFR) AF: 0.0874 AC: 2101 AN: 24046

American (AMR) AF: 0.311 AC: 9173 AN: 29490

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 3837 AN: 16500

East Asian (EAS) AF: 0.559 AC: 18712 AN: 33484

South Asian (SAS) AF: 0.245 AC: 18050 AN: 73696

European-Finnish (FIN) AF: 0.395 AC: 17016 AN: 43090

Middle Eastern (MID) AF: 0.205 AC: 924 AN: 4502

European-Non Finnish (NFE) AF: 0.296 AC: 285310 AN: 964084

Other (OTH) AF: 0.309 AC: 14722 AN: 47668

GnomAD4 genome AF: 0.230 AC: 32211 AN: 140116 Hom.: 4237 Cov.: 26 AF XY: 0.238 AC XY: 16033 AN XY: 67414

African (AFR) AF: 0.0830 AC: 3097 AN: 37324

American (AMR) AF: 0.283 AC: 3659 AN: 12930

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 605 AN: 3388

East Asian (EAS) AF: 0.476 AC: 2207 AN: 4634

South Asian (SAS) AF: 0.259 AC: 1062 AN: 4098

European-Finnish (FIN) AF: 0.383 AC: 3386 AN: 8844

Middle Eastern (MID) AF: 0.197 AC: 52 AN: 264

European-Non Finnish (NFE) AF: 0.267 AC: 17554 AN: 65814

Other (OTH) AF: 0.230 AC: 447 AN: 1940

Alfa AF: 0.244 Hom.: 16444

Bravo AF: 0.209

TwinsUK AF: 0.263 AC: 974

ALSPAC AF: 0.259 AC: 998

ESP6500AA AF: 0.0778 AC: 307

ESP6500EA AF: 0.254 AC: 2109

ExAC AF: 0.259 AC: 31247

Asia WGS AF: 0.344 AC: 1197 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 10 (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.092
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
Polyphen		0.026	B
Vest4		0.020
MPC		0.074
ClinPred		0.0055	T
GERP RS		2.2
Varity_R		0.037
gMVP		0.36
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2278792; hg19: chr18-29122799; COSMIC: COSV55203380;