rs151178348
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_002230.4(JUP):c.2207C>T(p.Pro736Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,609,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P736P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 0 hom. )
Consequence
JUP
NM_002230.4 missense
NM_002230.4 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 2.70
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.106607765).
BP6
Variant 17-41755775-G-A is Benign according to our data. Variant chr17-41755775-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45847.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=9, Benign=1}. Variant chr17-41755775-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00021 (32/152280) while in subpopulation NFE AF= 0.000397 (27/68014). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| JUP | NM_002230.4 | c.2207C>T | p.Pro736Leu | missense_variant | 14/14 | ENST00000393931.8 | NP_002221.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| JUP | ENST00000393931.8 | c.2207C>T | p.Pro736Leu | missense_variant | 14/14 | 1 | NM_002230.4 | ENSP00000377508.3 | ||
| JUP | ENST00000310706.9 | c.2207C>T | p.Pro736Leu | missense_variant | 14/15 | 1 | ENSP00000311113.5 | |||
| JUP | ENST00000393930.5 | c.2207C>T | p.Pro736Leu | missense_variant | 14/15 | 5 | ENSP00000377507.1 |
Frequencies
GnomAD3 genomes 0.000210 AC: 32AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000263 AC: 65AN: 247486Hom.: 0 AF XY: 0.000276 AC XY: 37AN XY: 133828
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GnomAD4 exome AF: 0.000253 AC: 368AN: 1456816Hom.: 0 Cov.: 31 AF XY: 0.000272 AC XY: 197AN XY: 724242
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GnomAD4 genome 0.000210 AC: 32AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74454
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 17, 2020 | The p.Pro736Leu variant (rs151178348) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.05 percent in the European Non-Finnish population (identified on 58 out of 125,094 chromosomes) and has been reported to the ClinVar database (Variation ID: 45847). The proline at position 736 is weakly conserved and computational analyses of the effects of the p.Pro736Leu variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro736Leu variant with certainty. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Mar 15, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 12, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2024 | Identified in a patient with Brugada syndrome and a patient with sudden unexplained death (SUD) in published literature (PMID: 26220970, 29334134, 29350269); Identified in patient with epidermolysis bullosa who also harbored several other variants including two COL7A1 variants (PMID: 29334134); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26220970, 29350269, 29334134) - |
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 736 of the JUP protein (p.Pro736Leu). This variant is present in population databases (rs151178348, gnomAD 0.05%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 45847). 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. 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 10, 2021 | - - |
not specified Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 01, 2015 | The p.Pro736Leu variant in JUP has been identified by our laboratory in 4 indivi duals (1 child with HCM, 1 adult and 1 child with DCM, and 1 child with RCM), 2 of whom carried clinically significant variants in other genes. This variant has also been identified in 0.04% (28/64990) of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs151178348). Proline (Pro) at position 736 is not conserved in evolution and 1 mammal (Tenre c) carries a leucine (Leu) at this position, raising the possibility that this c hange may be tolerated. In summary, the clinical significance of the p.Pro736Leu variant is uncertain. - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 18, 2023 | Variant summary: JUP c.2207C>T (p.Pro736Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 247486 control chromosomes. The observed variant frequency is approximately 42 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06), strongly suggesting that the variant is benign. c.2207C>T has been reported in the literature in individuals affected with Brugada Syndrome and sudden unexplained death (DiResta_2015, Neubauer_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Naxos disease Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Arrhythmogenic right ventricular dysplasia 12 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Left ventricular noncompaction cardiomyopathy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Jul 23, 2014 | - - |
Cardiovascular phenotype Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2022 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;.;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;B
Vest4
MVP
MPC
0.49
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at