rs912124448

chr18-31089484-C-Gchr18-31089484-C-T

Variant summary

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

The NM_024422.6(DSC2):c.585G>C(p.Leu195Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L195S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.270

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.585G>C	p.Leu195Phe	missense_variant	5/16	ENST00000280904.11
DSC2	NM_004949.5	c.585G>C	p.Leu195Phe	missense_variant	5/17
DSC2	NM_001406506.1	c.156G>C	p.Leu52Phe	missense_variant	5/16
DSC2	NM_001406507.1	c.156G>C	p.Leu52Phe	missense_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.585G>C	p.Leu195Phe	missense_variant	5/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.585G>C	p.Leu195Phe	missense_variant	5/17	1
DSC2	ENST00000648081.1	c.156G>C	p.Leu52Phe	missense_variant	6/17
DSC2	ENST00000682357.1	c.156G>C	p.Leu52Phe	missense_variant	5/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 14, 2021

This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DSC2-related conditions. This sequence change replaces leucine with phenylalanine at codon 195 of the DSC2 protein (p.Leu195Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 15, 2020

This missense variant replaces leucine with phenylalanine at codon 195 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.61
MutPred		0.55		Gain of catalytic residue at L195 (P = 0.0052);Gain of catalytic residue at L195 (P = 0.0052);.;
MVP		0.70
MPC		0.43
ClinPred		0.95	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.78

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: rs912124448; hg19: chr18-28669447;