dbSNP rs144242114: DSC2:p.Arg450Arg (chr18-31080266-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_024422.6(DSC2):c.1350A>G(p.Arg450Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,090 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 10 hom. )

Consequence

DSC2
NM_024422.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.00500

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 18-31080266-T-C is Benign according to our data. Variant chr18-31080266-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.005 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00265 (403/152284) while in subpopulation NFE AF = 0.00409 (278/68014). AF 95% confidence interval is 0.00369. There are 1 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR,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.1350A>G	p.Arg450Arg	synonymous	Exon 10 of 16	NP_077740.1	Q02487-1
DSC2	NM_004949.5		c.1350A>G	p.Arg450Arg	synonymous	Exon 10 of 17	NP_004940.1	Q02487-2
DSC2	NM_001406506.1		c.921A>G	p.Arg307Arg	synonymous	Exon 10 of 16	NP_001393435.1	A0A3B3ISU0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSC2	ENST00000280904.11	TSL:1 MANE Select	c.1350A>G	p.Arg450Arg	synonymous	Exon 10 of 16	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081.8	TSL:1	c.1350A>G	p.Arg450Arg	synonymous	Exon 10 of 17	ENSP00000251081.6	Q02487-2
DSC2	ENST00000713707.1		c.1350A>G	p.Arg450Arg	synonymous	Exon 10 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00409

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00313

AC:

786

AN:

251042

AF XY:

0.00315

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00336

AC:

4911

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

2395

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33478

American (AMR)

AF:

0.00322

AC:

144

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00941

AC:

246

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000649

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00371

AC:

4130

AN:

1111976

Other (OTH)

AF:

0.00354

AC:

214

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

291

582

873

1164

1455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<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:

0.00265

AC:

403

AN:

152284

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41572

American (AMR)

AF:

0.00242

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00409

AC:

278

AN:

68014

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

108

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:

0.00231

Hom.:

Bravo

AF:

0.00277

EpiCase

AF:

0.00387

EpiControl

AF:

0.00415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arrhythmogenic right ventricular dysplasia 11 (6)

not specified (6)

Cardiomyopathy (4)

not provided (2)

DSC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.4

(source)

DANN

Benign

0.74

PhyloP100

0.0050

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over