Genetic Variant DSG2:c.45+4757G>A (chr18-31503053-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001943.5(DSG2):c.45+4757G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 152,168 control chromosomes in the GnomAD database, including 1,493 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.088 ( 1493 hom., cov: 32)

Consequence

DSG2
NM_001943.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.241

Publications

3 publications found

Variant links:

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)

DSG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 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.45+4757G>A		intron	N/A	NP_001934.2	Q14126

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DSG2	ENST00000261590.13	TSL:1 MANE Select	c.45+4757G>A	intron	N/A	ENSP00000261590.8	Q14126
DSG2	ENST00000713817.1		c.-140+4757G>A	intron	N/A	ENSP00000519121.1	A0AAQ5BGZ7
DSG2	ENST00000713819.1		c.-178+4757G>A	intron	N/A	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes

AF:

0.0879

AC:

13371

AN:

152050

Hom.:

1498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.0306

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.0602

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0880

AC:

13386

AN:

152168

Hom.:

1493

Cov.:

AF XY:

0.0873

AC XY:

6497

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.263

AC:

10885

AN:

41466

American (AMR)

AF:

0.0384

AC:

588

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.0307

AC:

159

AN:

5186

South Asian (SAS)

AF:

0.123

AC:

593

AN:

4822

European-Finnish (FIN)

AF:

0.0121

AC:

128

AN:

10586

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0128

AC:

871

AN:

68012

Other (OTH)

AF:

0.0596

AC:

126

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

511

1023

1534

2046

2557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0302

Hom.:

271

Bravo

AF:

0.0954

Asia WGS

AF:

0.0960

AC:

335

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.37

(source)

DANN

Benign

0.42

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over