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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001943.5(DSG2):c.523+24delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 134,440 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 3 hom., cov: 32)

Exomes 𝑓: 0.33 ( 0 hom. )

Failed GnomAD Quality Control

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 -12 ACMG points.

BP6

Variant 18-31521252-CT-C is Benign according to our data. Variant chr18-31521252-CT-C is described in ClinVar as Benign. ClinVar VariationId is 188448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Frequencies

GnomAD3 genomes

AF:

0.00715

AC:

961

AN:

134442

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00535

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.00690

Gnomad NFE

AF:

0.00339

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.397

AC:

50035

AN:

126002

AF XY:

0.404

show subpopulations

Gnomad AFR exome

AF:

0.365

Gnomad AMR exome

AF:

0.430

Gnomad ASJ exome

AF:

0.430

Gnomad EAS exome

AF:

0.415

Gnomad FIN exome

AF:

0.357

Gnomad NFE exome

AF:

0.383

Gnomad OTH exome

AF:

0.405

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.335

AC:

324967

AN:

971340

Hom.:

Cov.:

AF XY:

0.340

AC XY:

163915

AN XY:

482352

show subpopulations

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

African (AFR)

AF:

0.339

AC:

6960

AN:

20556

American (AMR)

AF:

0.368

AC:

10185

AN:

27688

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

6725

AN:

17634

East Asian (EAS)

AF:

0.388

AC:

10280

AN:

26510

South Asian (SAS)

AF:

0.368

AC:

20058

AN:

54468

European-Finnish (FIN)

AF:

0.338

AC:

11865

AN:

35096

Middle Eastern (MID)

AF:

0.298

AC:

1130

AN:

3790

European-Non Finnish (NFE)

AF:

0.327

AC:

243779

AN:

745520

Other (OTH)

AF:

0.349

AC:

13985

AN:

40078

⚠️ 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: 0.274

Heterozygous variant carriers

30450

60900

91349

121799

152249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

8686

17372

26058

34744

43430

<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:

0.00716

AC:

963

AN:

134440

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

496

AN XY:

65022

show subpopulations

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

African (AFR)

AF:

0.0120

AC:

446

AN:

37256

American (AMR)

AF:

0.00550

AC:

AN:

13102

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3178

East Asian (EAS)

AF:

0.0156

AC:

AN:

4610

South Asian (SAS)

AF:

0.00291

AC:

AN:

4120

European-Finnish (FIN)

AF:

0.0173

AC:

133

AN:

7672

Middle Eastern (MID)

AF:

0.00758

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.00340

AC:

209

AN:

61550

Other (OTH)

AF:

0.00327

AC:

AN:

1834

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.400

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.108

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

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-CTTT

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