18-31069138-C-T

Variant names:

• chr18-31069138-C-T
• NM_024422.6:c.2264G>A

Variant summary

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

The NM_024422.6(DSC2):​c.2264G>A​(p.Gly755Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0430

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=0.10088655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2264G>A	p.Gly755Asp	missense_variant	Exon 15 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2264G>A	p.Gly755Asp	missense_variant	Exon 15 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1835G>A	p.Gly612Asp	missense_variant	Exon 15 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1835G>A	p.Gly612Asp	missense_variant	Exon 15 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2264G>A	p.Gly755Asp	missense_variant	Exon 15 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2264G>A	p.Gly755Asp	missense_variant	Exon 15 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1835G>A	p.Gly612Asp	missense_variant	Exon 16 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1835G>A	p.Gly612Asp	missense_variant	Exon 15 of 16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727218

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Jun 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.67
DEOGEN2	Benign	0.062	T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.068
Sift	Benign	0.48	T;T;.
Sift4G	Benign	0.26	T;T;.
Polyphen		0.026	B;B;.
Vest4		0.16
MutPred		0.46		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;
MVP		0.62
MPC		0.10
ClinPred		0.057	T
GERP RS		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.72

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: chr18-28649104;