18-31070728-C-T

Variant names:

• chr18-31070728-C-T
• rs753775769
• NM_024422.6:c.2248G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.2248G>A​(p.Val750Met) variant causes a missense, splice region 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. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V750V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense, splice_region
• Scores: Splicing: ADA: 0.00007223
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.286
• Publications: 0 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):

• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09763828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2248G>A	p.Val750Met	missense_variant, splice_region_variant	Exon 14 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2248G>A	p.Val750Met	missense_variant, splice_region_variant	Exon 14 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1819G>A	p.Val607Met	missense_variant, splice_region_variant	Exon 14 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1819G>A	p.Val607Met	missense_variant, splice_region_variant	Exon 14 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2248G>A	p.Val750Met	missense_variant, splice_region_variant	Exon 14 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 750 of the DSC2 protein (p.Val750Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 566877). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.056	T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		0.29
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.84	N;N;.
REVEL	Benign	0.024
Sift	Benign	0.29	T;T;.
Sift4G	Benign	0.18	T;T;.
Polyphen		0.059	B;B;.
Vest4		0.29
MutPred		0.26		Loss of methylation at K749 (P = 0.0726);Loss of methylation at K749 (P = 0.0726);.;
MVP		0.57
MPC		0.090
ClinPred		0.16	T
GERP RS		2.9
Varity_R		0.023
gMVP		0.34
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.0020
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: rs753775769; hg19: chr18-28650694;