Genetic Variant DSG2:c.523+24dupT (chr18-31521252-C-CT) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_001943.5(DSG2):c.523+24dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,334,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.037 ( 0 hom. )

Consequence

DSG2
NM_001943.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.123

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant 18-31521252-C-CT is Benign according to our data. Variant chr18-31521252-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1284866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00148 (200/134688) while in subpopulation AFR AF = 0.00223 (83/37264). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.523+24dupT		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.523+24dupT	intron	N/A	ENSP00000261590.8	Q14126
DSG2	ENST00000713817.1		c.514+24dupT	intron	N/A	ENSP00000519121.1	A0AAQ5BGZ7
DSG2	ENST00000713819.1		c.514+24dupT	intron	N/A	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

197

AN:

134690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000610

Gnomad ASJ

AF:

0.00126

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00121

Gnomad FIN

AF:

0.00284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.000547

GnomAD2 exomes

AF:

0.0319

AC:

4020

AN:

126002

AF XY:

0.0303

show subpopulations

Gnomad AFR exome

AF:

0.0171

Gnomad AMR exome

AF:

0.0316

Gnomad ASJ exome

AF:

0.0332

Gnomad EAS exome

AF:

0.0252

Gnomad FIN exome

AF:

0.0564

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0375

AC:

45003

AN:

1200166

Hom.:

Cov.:

AF XY:

0.0361

AC XY:

21657

AN XY:

600272

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0270

AC:

699

AN:

25866

American (AMR)

AF:

0.0259

AC:

885

AN:

34134

Ashkenazi Jewish (ASJ)

AF:

0.0281

AC:

625

AN:

22212

East Asian (EAS)

AF:

0.0237

AC:

816

AN:

34456

South Asian (SAS)

AF:

0.0311

AC:

2156

AN:

69270

European-Finnish (FIN)

AF:

0.0342

AC:

1470

AN:

43002

Middle Eastern (MID)

AF:

0.0241

AC:

110

AN:

4556

European-Non Finnish (NFE)

AF:

0.0398

AC:

36480

AN:

916556

Other (OTH)

AF:

0.0352

AC:

1762

AN:

50114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

5443

10886

16330

21773

27216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1614

3228

4842

6456

8070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00148

AC:

200

AN:

134688

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

106

AN XY:

65180

show subpopulations

African (AFR)

AF:

0.00223

AC:

AN:

37264

American (AMR)

AF:

0.000685

AC:

AN:

13134

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

3174

East Asian (EAS)

AF:

0.00173

AC:

AN:

4620

South Asian (SAS)

AF:

0.00146

AC:

AN:

4120

European-Finnish (FIN)

AF:

0.00284

AC:

AN:

7742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

61678

Other (OTH)

AF:

0.000544

AC:

AN:

1838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0159

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Arrhythmogenic right ventricular dysplasia 10 (1)

Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism

(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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18-31521252-CTTTT-CTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over