18-31521252-CTTTT-CTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001943.5(DSG2):c.523+23_523+24delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0073 in 1,349,226 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 3 hom. )

Consequence

DSG2
NM_001943.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

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 -16 ACMG points.

BP6

Variant 18-31521252-CTT-C is Benign according to our data. Variant chr18-31521252-CTT-C is described in ClinVar as Benign. ClinVar VariationId is 466344.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 = 0.00387 (521/134684) while in subpopulation NFE AF = 0.00635 (392/61700). AF 95% confidence interval is 0.00583. There are 3 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR 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.523+23_523+24delTT		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+23_523+24delTT	intron	N/A	ENSP00000261590.8	Q14126
DSG2	ENST00000713817.1		c.514+23_514+24delTT	intron	N/A	ENSP00000519121.1	A0AAQ5BGZ7
DSG2	ENST00000713819.1		c.514+23_514+24delTT	intron	N/A	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes

AF:

0.00387

AC:

521

AN:

134686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000752

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00175

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000216

Gnomad SAS

AF:

0.000724

Gnomad FIN

AF:

0.00894

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00635

Gnomad OTH

AF:

0.00274

GnomAD2 exomes

AF:

0.00983

AC:

1238

AN:

126002

AF XY:

0.00968

show subpopulations

Gnomad AFR exome

AF:

0.00334

Gnomad AMR exome

AF:

0.00847

Gnomad ASJ exome

AF:

0.00251

Gnomad EAS exome

AF:

0.00360

Gnomad FIN exome

AF:

0.0189

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.00668

GnomAD4 exome

AF:

0.00768

AC:

9330

AN:

1214542

Hom.:

AF XY:

0.00744

AC XY:

4523

AN XY:

607834

show subpopulations

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

African (AFR)

AF:

0.00353

AC:

AN:

25814

American (AMR)

AF:

0.00684

AC:

234

AN:

34224

Ashkenazi Jewish (ASJ)

AF:

0.00271

AC:

AN:

22504

East Asian (EAS)

AF:

0.00223

AC:

AN:

34934

South Asian (SAS)

AF:

0.00303

AC:

215

AN:

70874

European-Finnish (FIN)

AF:

0.0135

AC:

586

AN:

43254

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

4632

European-Non Finnish (NFE)

AF:

0.00832

AC:

7716

AN:

927582

Other (OTH)

AF:

0.00656

AC:

333

AN:

50724

⚠️ 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: 0.341

Heterozygous variant carriers

656

1312

1967

2623

3279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.00387

AC:

521

AN:

134684

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

262

AN XY:

65176

show subpopulations

African (AFR)

AF:

0.000751

AC:

AN:

37264

American (AMR)

AF:

0.00175

AC:

AN:

13122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3178

East Asian (EAS)

AF:

0.000216

AC:

AN:

4620

South Asian (SAS)

AF:

0.000728

AC:

AN:

4122

European-Finnish (FIN)

AF:

0.00894

AC:

AN:

7720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.00635

AC:

392

AN:

61700

Other (OTH)

AF:

0.00272

AC:

AN:

1838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

104

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:

0.00579

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Arrhythmogenic right ventricular dysplasia 10 (1)

Cardiomyopathy (1)

not specified (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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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