rs397517299

Positions:

• chr17-41757709-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002230.4(JUP):​c.1849G>A​(p.Ala617Thr) 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 benign outcome for this variant. 12/21 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)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.95

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35983235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.1849G>A	p.Ala617Thr	missense_variant	11/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.1849G>A	p.Ala617Thr	missense_variant	11/14	1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9	c.1849G>A	p.Ala617Thr	missense_variant	11/15	1		ENSP00000311113	P1
JUP	ENST00000393930.5	c.1849G>A	p.Ala617Thr	missense_variant	11/15	5		ENSP00000377507	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 617 of the JUP protein (p.Ala617Thr). This variant has not been reported in the literature in individuals affected with JUP-related conditions. 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: 45841). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2013

The Ala617Thr variant in JUP has not been previously reported in the literature or identified by our laboratory. The frequency of this variant in large European American and African American populations cannot be determined from the NHLBI E xome Sequencing Project (http://evs.gs.washington.edu/EVS/), because coverage at this position was insufficient or unavailable. Computational analyses (biochemi cal amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact the protein, though this information is not pre dictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Ala617Thr variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T
Eigen	Benign	0.012
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.095
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.33	B;B;B
Vest4		0.53
MutPred		0.45		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.86
MPC		0.60
ClinPred		0.82	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.38

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: rs397517299; hg19: chr17-39913961;