rs758646191

Variant names:

• chr18-31071734-C-A
• rs758646191
• NM_024422.6:c.1996G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-31071734-C-A
• chr18-31071734-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024422.6(DSC2):​c.1996G>T​(p.Val666Phe) variant causes a missense change involving the alteration of a non-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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V666I) has been classified 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: 2.21
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1996G>T	p.Val666Phe	missense_variant	Exon 13 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1996G>T	p.Val666Phe	missense_variant	Exon 13 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1567G>T	p.Val523Phe	missense_variant	Exon 13 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1567G>T	p.Val523Phe	missense_variant	Exon 13 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1996G>T	p.Val666Phe	missense_variant	Exon 13 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Aug 15, 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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.8	H;H;.
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D;D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.82
MutPred		0.50		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.88
MPC		0.49
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.52
gMVP		0.98
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs758646191; hg19: chr18-28651700;