dbSNP rs144799937: DSC2:p.Glu102Lys (chr18-31092151-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024422.6(DSC2):c.304G>A(p.Glu102Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,078 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:15

Conservation

PhyloP100: 0.844

Publications

20 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01640156).

BP6

Variant 18-31092151-C-T is Benign according to our data. Variant chr18-31092151-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46189.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00075 (114/152050) while in subpopulation NFE AF = 0.00134 (91/68026). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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.304G>A	p.Glu102Lys	missense	Exon 3 of 16	NP_077740.1	Q02487-1
DSC2	NM_004949.5		c.304G>A	p.Glu102Lys	missense	Exon 3 of 17	NP_004940.1	Q02487-2
DSC2	NM_001406506.1		c.-126G>A		5_prime_UTR	Exon 3 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.304G>A	p.Glu102Lys	missense	Exon 3 of 16	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081.8	TSL:1	c.304G>A	p.Glu102Lys	missense	Exon 3 of 17	ENSP00000251081.6	Q02487-2
DSC2	ENST00000713707.1		c.304G>A	p.Glu102Lys	missense	Exon 3 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes

AF:

0.000750

AC:

114

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000777

AC:

195

AN:

250872

AF XY:

0.000708

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.00128

AC:

1867

AN:

1461028

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

930

AN XY:

726780

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33440

American (AMR)

AF:

0.000134

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.000534

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00149

AC:

1658

AN:

1111506

Other (OTH)

AF:

0.00124

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.000750

AC:

114

AN:

152050

Hom.:

Cov.:

AF XY:

0.000835

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41382

American (AMR)

AF:

0.000393

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68026

Other (OTH)

AF:

0.000958

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00130

Hom.:

Bravo

AF:

0.000748

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arrhythmogenic right ventricular dysplasia 11 (4)

not provided (4)

not specified (4)

Cardiomyopathy (2)

Cardiovascular phenotype (2)

Arrhythmogenic right ventricular cardiomyopathy (1)

DSC2-related disorder (1)

Familial isolated arrhythmogenic right ventricular dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.57

M_CAP

Benign

0.019

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

0.84

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.58

REVEL

Benign

0.28

Sift

Benign

0.42

Sift4G

Benign

0.42

Polyphen

0.016

Vest4

0.73

MVP

0.66

MPC

0.096

ClinPred

0.010

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.099

gMVP

0.32

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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