rs191143292

Variant names:

• chr18-31521193-T-G
• rs191143292
• NM_001943.5:c.473T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-31521193-T-G
• chr18-31521193-T-A
• chr18-31521193-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001943.5(DSG2):​c.473T>G​(p.Val158Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00712 in 1,613,620 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts 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. V158L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (48 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 3.83
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021739274).
• BP6: Variant 18-31521193-T-G is Benign according to our data. Variant chr18-31521193-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00525 (797/151862) while in subpopulation NFE AF = 0.00806 (548/67950). AF 95% confidence interval is 0.00751. There are 3 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.473T>G	p.Val158Gly	missense	Exon 5 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.473T>G	p.Val158Gly	missense	Exon 5 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.464T>G	p.Val155Gly	missense	Exon 6 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.464T>G	p.Val155Gly	missense	Exon 7 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 797 AN: 151768 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00539 AC: 1344 AN: 249296 AF XY: 0.00529

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00863

Gnomad NFE exome AF: 0.00809

Gnomad OTH exome AF: 0.00661

GnomAD4 exome AF: 0.00731 AC: 10686 AN: 1461758 Hom.: 48 Cov.: 33 AF XY: 0.00708 AC XY: 5148 AN XY: 727178

African (AFR) AF: 0.00102 AC: 34 AN: 33474

American (AMR) AF: 0.00429 AC: 192 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.00139 AC: 120 AN: 86252

European-Finnish (FIN) AF: 0.00854 AC: 456 AN: 53416

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00855 AC: 9507 AN: 1111932

Other (OTH) AF: 0.00560 AC: 338 AN: 60390

GnomAD4 genome AF: 0.00525 AC: 797 AN: 151862 Hom.: 3 Cov.: 32 AF XY: 0.00511 AC XY: 379 AN XY: 74186

African (AFR) AF: 0.00162 AC: 67 AN: 41440

American (AMR) AF: 0.00288 AC: 44 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4788

European-Finnish (FIN) AF: 0.00801 AC: 84 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00806 AC: 548 AN: 67950

Other (OTH) AF: 0.00428 AC: 9 AN: 2102

Alfa AF: 0.00327 Hom.: 14

Bravo AF: 0.00498

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00240 AC: 9

ESP6500EA AF: 0.00788 AC: 65

ExAC AF: 0.00537 AC: 649

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00676

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Arrhythmogenic right ventricular cardiomyopathy (4)
-	-	4	not provided (4)
-	-	1	Arrhythmogenic right ventricular dysplasia 1 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 10 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary dilated cardiomyopathy;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Benign	0.71
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		3.8
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.050	B
Vest4		0.63
MVP		0.68
MPC		0.48
ClinPred		0.15	T
GERP RS		3.2
Varity_R		0.93
gMVP		0.86
Mutation Taster		=85/15	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: rs191143292; hg19: chr18-29101156; COSMIC: COSV55196903;