17-41767542-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002230.4(JUP):c.746C>G(p.Thr249Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T249M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.99

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JUP	NM_002230.4	c.746C>G	p.Thr249Arg	missense_variant	5/14	ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8	c.746C>G	p.Thr249Arg	missense_variant	5/14	1	NM_002230.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;D;.;T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.95
MutPred		0.79		Gain of methylation at T249 (P = 0.1234);Gain of methylation at T249 (P = 0.1234);Gain of methylation at T249 (P = 0.1234);Gain of methylation at T249 (P = 0.1234);Gain of methylation at T249 (P = 0.1234);Gain of methylation at T249 (P = 0.1234);
MVP		0.96
MPC		0.51
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs377612199; hg19: chr17-39923794;