rs199616533

Positions:

• chr18-31071671-C-G
• chr18-31071671-C-T

Variant summary

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

The NM_024422.6(DSC2):​c.2059G>C​(p.Gly687Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.479

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=0.11400056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2059G>C	p.Gly687Arg	missense_variant	13/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2059G>C	p.Gly687Arg	missense_variant	13/17		NP_004940.1
DSC2	NM_001406506.1	c.1630G>C	p.Gly544Arg	missense_variant	13/16		NP_001393435.1
DSC2	NM_001406507.1	c.1630G>C	p.Gly544Arg	missense_variant	13/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2059G>C	p.Gly687Arg	missense_variant	13/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2059G>C	p.Gly687Arg	missense_variant	13/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1630G>C	p.Gly544Arg	missense_variant	14/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1630G>C	p.Gly544Arg	missense_variant	13/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 137870 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 137870 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 67340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 25, 2016

The p.Gly687Arg variant in DSC2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Glycine (Gly) at position 68 7 is not conserved in mammals or evolutionarily distant species, raising the pos sibility that a change at this position may be tolerated. Additional computation al prediction tools suggest that the p.Gly687Arg variant may not impact the prot ein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Gly687Arg variant is uncertain. -

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 09, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 505392). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 687 of the DSC2 protein (p.Gly687Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.3
DANN	Benign	0.60
DEOGEN2	Benign	0.071	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.040	N;N;.
REVEL	Benign	0.11
Sift	Benign	0.33	T;T;.
Sift4G	Benign	0.47	T;T;.
Polyphen		0.013	B;B;.
Vest4		0.24
MutPred		0.60		Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);.;
MVP		0.37
MPC		0.13
ClinPred		0.072	T
GERP RS		-6.9
Varity_R		0.046
gMVP		0.43

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: rs199616533; hg19: chr18-28651637;