rs794729040

Positions:

• chr17-41767479-A-C
• chr17-41767479-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000393931.8(JUP):​c.809T>G​(p.Leu270Arg) variant causes a missense change involving the alteration of a 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L270Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: JUP ENST00000393931.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 9.31

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.809T>G	p.Leu270Arg	missense_variant	5/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.809T>G	p.Leu270Arg	missense_variant	5/14	1	NM_002230.4	ENSP00000377508	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D;.;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;.;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.9	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.82
MutPred		0.85		Gain of methylation at L270 (P = 0.0191);Gain of methylation at L270 (P = 0.0191);Gain of methylation at L270 (P = 0.0191);Gain of methylation at L270 (P = 0.0191);Gain of methylation at L270 (P = 0.0191);Gain of methylation at L270 (P = 0.0191);
MVP		0.87
MPC		0.40
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39923731;