rs1285789744
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_002230.4(JUP):c.2179G>A(p.Asp727Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,612,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002230.4 missense
Scores
Clinical Significance
Conservation
Publications
- arrhythmogenic right ventricular dysplasia 12Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- inherited epidermolysis bullosaInheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
- Naxos diseaseInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- lethal acantholytic epidermolysis bullosaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
JUP | NM_002230.4 | c.2179G>A | p.Asp727Asn | missense_variant | Exon 14 of 14 | ENST00000393931.8 | NP_002221.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JUP | ENST00000393931.8 | c.2179G>A | p.Asp727Asn | missense_variant | Exon 14 of 14 | 1 | NM_002230.4 | ENSP00000377508.3 | ||
JUP | ENST00000310706.9 | c.2179G>A | p.Asp727Asn | missense_variant | Exon 14 of 15 | 1 | ENSP00000311113.5 | |||
JUP | ENST00000393930.5 | c.2179G>A | p.Asp727Asn | missense_variant | Exon 14 of 15 | 5 | ENSP00000377507.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000280 AC: 7AN: 249860 AF XY: 0.0000148 show subpopulations
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1460760Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 726542 show subpopulations
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278 show subpopulations
ClinVar
Submissions by phenotype
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 727 of the JUP protein (p.Asp727Asn). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 518649). 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. -
not provided Benign:1
Reported as a variant of uncertain significance by two other clinical laboratories in ClinVar but additional evidence is not available (ClinVar Variant ID# 518649; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in one individual with hypertrophic cardiomyopathy (HCM); however, detailed clinical information was not provided (Lopes et al., 2015); This variant is associated with the following publications: (PMID: 25351510) -
Cardiovascular phenotype Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at