chr18-31070728-C-T

Position:

• chr18-31070728-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.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. 18/23 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 (★).

• 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

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=0.09763828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.2248G>A	p.Val750Met	missense_variant, splice_region_variant	14/16	ENST00000280904.11
DSC2	NM_004949.5	c.2248G>A	p.Val750Met	missense_variant, splice_region_variant	14/17
DSC2	NM_001406506.1	c.1819G>A	p.Val607Met	missense_variant, splice_region_variant	14/16
DSC2	NM_001406507.1	c.1819G>A	p.Val607Met	missense_variant, splice_region_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.2248G>A	p.Val750Met	missense_variant, splice_region_variant	14/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.2248G>A	p.Val750Met	missense_variant, splice_region_variant	14/17	1
DSC2	ENST00000648081.1	c.1819G>A	p.Val607Met	missense_variant, splice_region_variant	15/17
DSC2	ENST00000682357.1	c.1819G>A	p.Val607Met	missense_variant, splice_region_variant	14/16

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This variant is not present in population databases (gnomAD 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 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. ClinVar contains an entry for this variant (Variation ID: 566877). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. 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). -

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;.
MutationTaster	Benign	0.82	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs753775769; hg19: chr18-28650694;