chr18-31519887-G-A

Variant names:

• chr18-31519887-G-A
• rs121913013
• NM_001943.5:c.166G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_001943.5(DSG2):​c.166G>A​(p.Val56Met) variant causes a missense change. The variant allele was found at a frequency of 0.00244 in 1,614,130 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V56G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (8 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:23 O:1
• Conservation: PhyloP100: 6.62
• Publications: 30 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: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_001943.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.11316037).
• BP6: Variant 18-31519887-G-A is Benign according to our data. Variant chr18-31519887-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16818.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00179 (273/152258) while in subpopulation NFE AF = 0.00316 (215/68020). AF 95% confidence interval is 0.00281. There are 1 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.166G>A	p.Val56Met	missense	Exon 3 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.166G>A	p.Val56Met	missense	Exon 3 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713762.1		c.-369G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 15	ENSP00000519063.1	A0AAQ5BGT2
	DSG2	ENST00000713779.1		c.-369G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	ENSP00000519081.1	A0AAQ5BGT2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00189 AC: 471 AN: 249490 AF XY: 0.00187

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00251 AC: 3672 AN: 1461872 Hom.: 8 Cov.: 31 AF XY: 0.00243 AC XY: 1767 AN XY: 727238

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00199 AC: 89 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00307 AC: 3415 AN: 1111998

Other (OTH) AF: 0.00144 AC: 87 AN: 60396

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74440

African (AFR) AF: 0.000602 AC: 25 AN: 41548

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00316 AC: 215 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00262 Hom.: 5

Bravo AF: 0.00182

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000532 AC: 2

ESP6500EA AF: 0.00353 AC: 29

ExAC AF: 0.00187 AC: 226

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
1	2	2	Arrhythmogenic right ventricular dysplasia 10 (5)
-	-	5	not specified (5)
-	1	3	Arrhythmogenic right ventricular cardiomyopathy (4)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	Dilated cardiomyopathy 1BB (2)
-	-	1	DSG2-related disorder (1)
-	-	1	Long QT syndrome (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.51
MVP		0.71
MPC		0.40
ClinPred		0.045	T
GERP RS		5.2
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.12
gMVP		0.74
Mutation Taster		=90/10	polymorphism

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: rs121913013; hg19: chr18-29099850; COSMIC: COSV55198165;