chr18-31524754-A-G

Variant names:

• chr18-31524754-A-G
• rs752432726
• NM_001943.5:c.880A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BS1 BS2

The NM_001943.5(DSG2):​c.880A>G​(p.Lys294Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,614,090 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K294I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (2 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:11
• Conservation: PhyloP100: 4.20
• Publications: 6 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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1BB

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000363 (53/1461868) while in subpopulation MID AF = 0.00104 (6/5768). AF 95% confidence interval is 0.000453. There are 2 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.880A>G	p.Lys294Glu	missense	Exon 8 of 15	NP_001934.2	Q14126

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.880A>G	p.Lys294Glu	missense	Exon 8 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.871A>G	p.Lys291Glu	missense	Exon 9 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.871A>G	p.Lys291Glu	missense	Exon 10 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249384 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461868 Hom.: 2 Cov.: 35 AF XY: 0.0000454 AC XY: 33 AN XY: 727234

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112004

Other (OTH) AF: 0.000281 AC: 17 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.0000482 AC: 2 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
1	1	-	Arrhythmogenic right ventricular cardiomyopathy (2)
-	2	-	Cardiomyopathy (2)
-	1	-	Arrhythmogenic right ventricular dysplasia 10 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.62
MutPred		0.81		Loss of ubiquitination at K294 (P = 0.0326)
MVP		0.83
MPC		0.47
ClinPred		0.42	T
GERP RS		5.3
Varity_R		0.61
gMVP		0.74
Mutation Taster		=27/73	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs752432726; hg19: chr18-29104717;