NM_024422.6:c.721C>G

Variant names:

• chr18-31087723-G-C
• NM_024422.6:c.721C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024422.6(DSC2):​c.721C>G​(p.Pro241Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.27

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.721C>G	p.Pro241Ala	missense_variant	Exon 6 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.721C>G	p.Pro241Ala	missense_variant	Exon 6 of 17		NP_004940.1
DSC2	NM_001406506.1	c.292C>G	p.Pro98Ala	missense_variant	Exon 6 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.292C>G	p.Pro98Ala	missense_variant	Exon 6 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.721C>G	p.Pro241Ala	missense_variant	Exon 6 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.721C>G	p.Pro241Ala	missense_variant	Exon 6 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.292C>G	p.Pro98Ala	missense_variant	Exon 7 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.292C>G	p.Pro98Ala	missense_variant	Exon 6 of 16			ENSP00000507826.1

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

Feb 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DSC2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 241 of the DSC2 protein (p.Pro241Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.1	D;D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.85
MutPred		0.77		Loss of catalytic residue at N239 (P = 0.0819);Loss of catalytic residue at N239 (P = 0.0819);.;
MVP		0.98
MPC		0.41
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28667686;