rs1555599683

Positions:

• chr17-41758722-G-T

Variant summary

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

The NM_002230.4(JUP):​c.1646C>A​(p.Pro549His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.73

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/exons	MANE	UniProt
JUP	NM_002230.4	c.1646C>A	p.Pro549His	missense_variant	9/14	ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8	c.1646C>A	p.Pro549His	missense_variant	9/14	1	NM_002230.4	P1
JUP	ENST00000310706.9	c.1646C>A	p.Pro549His	missense_variant	9/15	1		P1
JUP	ENST00000393930.5	c.1646C>A	p.Pro549His	missense_variant	9/15	5		P1
JUP	ENST00000585793.1	n.244C>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448478 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719514

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: 0.00

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 04, 2016

The p.Pro549His variant in JUP has not been previously reported in individuals w ith cardiomyopathy, and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Pro549His variant is uncertain. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

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 tolerated. ClinVar contains an entry for this variant (Variation ID: 505271). This variant has not been reported in the literature in individuals affected with JUP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 549 of the JUP protein (p.Pro549His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.052	T;T;T
Polyphen		0.27	B;B;B
Vest4		0.70
MutPred		0.38		Loss of glycosylation at T546 (P = 0.0733);Loss of glycosylation at T546 (P = 0.0733);Loss of glycosylation at T546 (P = 0.0733);
MVP		0.78
MPC		0.83
ClinPred		0.84	D
GERP RS		5.1
Varity_R		0.58
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs1555599683; hg19: chr17-39914974;