chr17-41757649-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_002230.4(JUP):c.1909C>T(p.Arg637Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R637H) has been classified as Likely benign.
Frequency
Consequence
NM_002230.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
JUP | NM_002230.4 | c.1909C>T | p.Arg637Cys | missense_variant | Exon 11 of 14 | ENST00000393931.8 | NP_002221.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JUP | ENST00000393931.8 | c.1909C>T | p.Arg637Cys | missense_variant | Exon 11 of 14 | 1 | NM_002230.4 | ENSP00000377508.3 | ||
JUP | ENST00000310706.9 | c.1909C>T | p.Arg637Cys | missense_variant | Exon 11 of 15 | 1 | ENSP00000311113.5 | |||
JUP | ENST00000393930.5 | c.1909C>T | p.Arg637Cys | missense_variant | Exon 11 of 15 | 5 | ENSP00000377507.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000403 AC: 10AN: 248158Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134474
GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461342Hom.: 0 Cov.: 38 AF XY: 0.0000729 AC XY: 53AN XY: 726942
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74466
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Identified in conjunction with additional variants in individuals referred for genetic testing at GeneDx; segregation data are limited at this time; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 179915; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2025 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 637 of the JUP protein (p.Arg637Cys). This variant is present in population databases (rs531732438, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of JUP-related conditions (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 179915). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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 | Jul 25, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 08, 2014 | The Arg637Cys variant in JUP has not been previously reported in individuals wit h cardiomyopathy. Data from large population studies is insufficient to assess t he frequency of this variant. Computational prediction tools and conservation an alysis suggest that the Arg637Cys variant may not impact the protein, though thi s information is not predictive enough to rule out pathogenicity. In summary, th e clinical significance of the Arg637Cys variant is uncertain. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2023 | This alteration is classified as likely 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at