rs368564000

Variant names:

• chr17-41764742-G-A
• rs368564000
• NM_002230.4:c.1129C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-41764742-G-A
• chr17-41764742-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002230.4(JUP):​c.1129C>T​(p.Arg377Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,024 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R377S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.34
• Publications: 4 publications found

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]

JUP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• inherited epidermolysis bullosa

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Naxos disease

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.1129C>T	p.Arg377Cys	missense_variant	Exon 7 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.1129C>T	p.Arg377Cys	missense_variant	Exon 7 of 14	1	NM_002230.4	ENSP00000377508.3
JUP	ENST00000310706.9	c.1129C>T	p.Arg377Cys	missense_variant	Exon 7 of 15	1		ENSP00000311113.5
JUP	ENST00000393930.5	c.1129C>T	p.Arg377Cys	missense_variant	Exon 7 of 15	5		ENSP00000377507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251252 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461024 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 726830

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5202

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jun 06, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R377C variant (also known as c.1129C>T), located in coding exon 6 of the JUP gene, results from a C to T substitution at nucleotide position 1129. The arginine at codon 377 is replaced by cysteine, an amino acid with highly dissimilar properties. Other alterations affecting the same amino acid, p.R377H (c.1130G>A) and p.R377S (c.1129C>A), have been reported in association with cardiomyopathy (Zhou X et al. Eur J Med Genet, 2015 Apr;58:258-65; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 377 of the JUP protein (p.Arg377Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 808262). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.3	M;M;M
PhyloP100		3.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.4	D;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.70		Loss of MoRF binding (P = 0.0118);Loss of MoRF binding (P = 0.0118);Loss of MoRF binding (P = 0.0118);
MVP		0.86
MPC		1.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.76
Mutation Taster		=27/73	disease causing

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: rs368564000; hg19: chr17-39920994;