rs1060502681

Variant names:

• chr17-41763089-C-T
• rs1060502681
• NM_002230.4:c.1391G>A

Variant summary

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

The NM_002230.4(JUP):​c.1391G>A​(p.Ser464Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.04

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.1391G>A	p.Ser464Asn	missense_variant	Exon 8 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.1391G>A	p.Ser464Asn	missense_variant	Exon 8 of 14	1	NM_002230.4	ENSP00000377508.3
JUP	ENST00000310706.9	c.1391G>A	p.Ser464Asn	missense_variant	Exon 8 of 15	1		ENSP00000311113.5
JUP	ENST00000393930.5	c.1391G>A	p.Ser464Asn	missense_variant	Exon 8 of 15	5		ENSP00000377507.1
JUP	ENST00000585793.1	n.-12G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Oct 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S464N variant (also known as c.1391G>A), located in coding exon 7 of the JUP gene, results from a G to A substitution at nucleotide position 1391. The serine at codon 464 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:1

Nov 24, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a JUP-related disease. This sequence change replaces serine with asparagine at codon 464 of the JUP protein (p.Ser464Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.12
Sift	Benign	0.057	T;T;T
Sift4G	Benign	0.074	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.67
MutPred		0.42		Loss of glycosylation at S464 (P = 0.0468);Loss of glycosylation at S464 (P = 0.0468);Loss of glycosylation at S464 (P = 0.0468);
MVP		0.57
MPC		1.2
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.81
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060502681; hg19: chr17-39919341;