18-31069010-G-C

Position:

• chr18-31069010-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.2392C>G​(p.Arg798Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R798Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16308305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2392C>G	p.Arg798Gly	missense_variant	15/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2392C>G	p.Arg798Gly	missense_variant	15/17		NP_004940.1
DSC2	NM_001406506.1	c.1963C>G	p.Arg655Gly	missense_variant	15/16		NP_001393435.1
DSC2	NM_001406507.1	c.1963C>G	p.Arg655Gly	missense_variant	15/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2392C>G	p.Arg798Gly	missense_variant	15/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2392C>G	p.Arg798Gly	missense_variant	15/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1963C>G	p.Arg655Gly	missense_variant	16/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1963C>G	p.Arg655Gly	missense_variant	15/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251166 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	0.0053	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Benign	0.17	T
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Benign	0.13
Sift	Benign	0.041	D;D;.
Sift4G	Uncertain	0.051	T;D;.
Polyphen		0.0030	B;B;.
Vest4		0.14
MutPred		0.27		Loss of methylation at R798 (P = 0.0385);Loss of methylation at R798 (P = 0.0385);.;
MVP		0.84
MPC		0.097
ClinPred		0.20	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs201548399; hg19: chr18-28648976;