18-31069009-C-T

Variant names:

• chr18-31069009-C-T
• rs61731921
• NM_024422.6:c.2393G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024422.6(DSC2):​c.2393G>A​(p.Arg798Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,613,980 control chromosomes in the GnomAD database, including 2,177 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R798L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (162 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2015 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.22
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018272996).
• BP6: Variant 18-31069009-C-T is Benign according to our data. Variant chr18-31069009-C-T is described in ClinVar as Benign. ClinVar VariationId is 36006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	NM_024422.6	MANE Select	c.2393G>A	p.Arg798Gln	missense	Exon 15 of 16	NP_077740.1	Q02487-1
	DSC2	NM_004949.5		c.2393G>A	p.Arg798Gln	missense	Exon 15 of 17	NP_004940.1	Q02487-2
	DSC2	NM_001406506.1		c.1964G>A	p.Arg655Gln	missense	Exon 15 of 16	NP_001393435.1	A0A3B3ISU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.2393G>A	p.Arg798Gln	missense	Exon 15 of 16	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.2393G>A	p.Arg798Gln	missense	Exon 15 of 17	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.2414G>A	p.Arg805Gln	missense	Exon 15 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes AF: 0.0380 AC: 5776 AN: 152020 Hom.: 163 Cov.: 32

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0701

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0482

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0471 AC: 11825 AN: 251172 AF XY: 0.0504

Gnomad AFR exome AF: 0.00732

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0509

Gnomad OTH exome AF: 0.0481

GnomAD4 exome AF: 0.0466 AC: 68150 AN: 1461842 Hom.: 2015 Cov.: 31 AF XY: 0.0481 AC XY: 35004 AN XY: 727222

African (AFR) AF: 0.00666 AC: 223 AN: 33480

American (AMR) AF: 0.0140 AC: 626 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 760 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39694

South Asian (SAS) AF: 0.0777 AC: 6700 AN: 86256

European-Finnish (FIN) AF: 0.113 AC: 6036 AN: 53410

Middle Eastern (MID) AF: 0.0321 AC: 185 AN: 5766

European-Non Finnish (NFE) AF: 0.0459 AC: 51038 AN: 1111984

Other (OTH) AF: 0.0425 AC: 2567 AN: 60394

GnomAD4 genome AF: 0.0379 AC: 5771 AN: 152138 Hom.: 162 Cov.: 32 AF XY: 0.0408 AC XY: 3034 AN XY: 74366

African (AFR) AF: 0.00833 AC: 346 AN: 41544

American (AMR) AF: 0.0163 AC: 249 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3466

East Asian (EAS) AF: 0.00233 AC: 12 AN: 5160

South Asian (SAS) AF: 0.0697 AC: 336 AN: 4818

European-Finnish (FIN) AF: 0.122 AC: 1290 AN: 10558

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0482 AC: 3275 AN: 67988

Other (OTH) AF: 0.0365 AC: 77 AN: 2110

Alfa AF: 0.0405 Hom.: 324

Bravo AF: 0.0274

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0407 AC: 157

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0452 AC: 389

ExAC AF: 0.0495 AC: 6006

Asia WGS AF: 0.0320 AC: 113 AN: 3478

EpiCase AF: 0.0429

EpiControl AF: 0.0438

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Arrhythmogenic right ventricular dysplasia 11 (5)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial isolated arrhythmogenic right ventricular dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.36
DANN	Benign	0.89
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.79	N
PhyloP100		-1.2
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.17
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Polyphen		0.0060	B
Vest4		0.031
MPC		0.085
ClinPred		0.0020	T
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.22
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61731921; hg19: chr18-28648975;