dbSNP rs200056085: DSC2:p.Ala897LysfsTer4 (chr18-31068033-T-TTC) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBS1BS2

The NM_024422.6(DSC2):c.2686_2687dupGA(p.Ala897LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0106 in 1,613,982 control chromosomes in the GnomAD database, including 114 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 103 hom. )

Consequence

DSC2
NM_024422.6 frameshift

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:21

Conservation

PhyloP100: 5.14

Publications

18 publications found

Variant links:

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

DSC2 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 11
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
familial isolated arrhythmogenic right ventricular dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00702 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 18-31068033-T-TTC is Benign according to our data. Variant chr18-31068033-T-TTC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46186.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 = 0.00872 (1327/152258) while in subpopulation NFE AF = 0.0146 (991/68012). AF 95% confidence interval is 0.0138. There are 11 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSC2	NM_024422.6	MANE Select	c.2686_2687dupGA	p.Ala897LysfsTer4	frameshift	Exon 16 of 16	NP_077740.1	Q02487-1
DSC2	NM_001406506.1		c.2257_2258dupGA	p.Ala754LysfsTer4	frameshift	Exon 16 of 16	NP_001393435.1	A0A3B3ISU0
DSC2	NM_004949.5		c.188_189dupGA		3_prime_UTR	Exon 17 of 17	NP_004940.1	Q02487-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSC2	ENST00000280904.11	TSL:1 MANE Select	c.2686_2687dupGA	p.Ala897LysfsTer4	frameshift	Exon 16 of 16	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081.8	TSL:1	c.188_189dupGA		3_prime_UTR	Exon 17 of 17	ENSP00000251081.6	Q02487-2
DSC2	ENST00000713707.1		c.2707_2708dupGA	p.Ala904LysfsTer4	frameshift	Exon 16 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes

AF:

0.00872

AC:

1327

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00623

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00915

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00843

AC:

2119

AN:

251230

AF XY:

0.00854

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00915

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.0108

AC:

15742

AN:

1461724

Hom.:

103

Cov.:

AF XY:

0.0106

AC XY:

7673

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33478

American (AMR)

AF:

0.00548

AC:

245

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.00340

AC:

293

AN:

86254

European-Finnish (FIN)

AF:

0.0103

AC:

552

AN:

53406

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0126

AC:

13968

AN:

1111922

Other (OTH)

AF:

0.00907

AC:

548

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

763

1526

2290

3053

3816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

494

988

1482

1976

2470

<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:

0.00872

AC:

1327

AN:

152258

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41578

American (AMR)

AF:

0.00622

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00915

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

991

AN:

68012

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

140

209

279

349

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:

0.0117

Hom.:

Bravo

AF:

0.00808

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0130

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Arrhythmogenic right ventricular dysplasia 11 (6)

not provided (3)

Cardiomyopathy (2)

Arrhythmogenic right ventricular cardiomyopathy (1)

Cardiovascular phenotype (1)

Familial isolated arrhythmogenic right ventricular dysplasia (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=136/64

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over