rs147109895

Variant names:

• chr18-31068134-C-T
• rs147109895
• NM_024422.6:c.2587G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_024422.6(DSC2):​c.2587G>A​(p.Gly863Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000555 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. G863E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 6.72
• Publications: 11 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19868788).
• BP6: Variant 18-31068134-C-T is Benign according to our data. Variant chr18-31068134-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46183.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000223 (34/152236) while in subpopulation NFE AF = 0.000323 (22/68018). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2587G>A	p.Gly863Arg	missense	Exon 16 of 16	NP_077740.1	Q02487-1
	DSC2	NM_001406506.1		c.2158G>A	p.Gly720Arg	missense	Exon 16 of 16	NP_001393435.1	A0A3B3ISU0
	DSC2	NM_004949.5		c.*89G>A		3_prime_UTR	Exon 17 of 17	NP_004940.1	Q02487-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.2587G>A	p.Gly863Arg	missense	Exon 16 of 16	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.*89G>A		3_prime_UTR	Exon 17 of 17	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.2608G>A	p.Gly870Arg	missense	Exon 16 of 16	ENSP00000519010.1	A0AAQ5BGP6

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251128 AF XY: 0.000332

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000590 AC: 862 AN: 1461814 Hom.: 1 Cov.: 31 AF XY: 0.000608 AC XY: 442 AN XY: 727198

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000683 AC: 760 AN: 1111984

Other (OTH) AF: 0.000497 AC: 30 AN: 60390

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74438

African (AFR) AF: 0.0000722 AC: 3 AN: 41534

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000456 Hom.: 0

Bravo AF: 0.000306

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not specified (4)
-	2	1	Arrhythmogenic right ventricular dysplasia 11 (3)
-	3	-	not provided (3)
-	-	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	Pathogenic	0.82
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.60		Loss of sheet (P = 0.0315)
MVP		0.93
MPC		0.47
ClinPred		0.60	D
GERP RS		5.9
Varity_R		0.62
gMVP		0.81
Mutation Taster		=67/33	polymorphism

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: rs147109895; hg19: chr18-28648100;