X-37793716-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000397.4(CYBB):c.389G>C(p.Arg130Pro) variant causes a missense change. 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 Pathogenic (★★).
Frequency
Consequence
NM_000397.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYBB | NM_000397.4 | c.389G>C | p.Arg130Pro | missense_variant | Exon 5 of 13 | ENST00000378588.5 | NP_000388.2 | |
CYBB | XM_047441855.1 | c.83G>C | p.Arg28Pro | missense_variant | Exon 4 of 12 | XP_047297811.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.389G>C | p.Arg130Pro | missense_variant | Exon 5 of 13 | 1 | NM_000397.4 | ENSP00000367851.4 | ||
ENSG00000250349 | ENST00000465127.1 | c.171+367716G>C | intron_variant | Intron 3 of 8 | 5 | ENSP00000417050.1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 21
ClinVar
Submissions by phenotype
Granulomatous disease, chronic, X-linked Pathogenic:2
Variant summary: CYBB c.389G>C (p.Arg130Pro) results in a non-conservative amino acid change located in the Ferric reductase transmembrane component-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. One out of 3 computational tools predict a significant impact on normal splicing, namely a disruption of the binding site for the SRSF6 (SRp55) splicing factor within the splicing-regulatory sequence in exon 5 of the CYBB gene. The variant was absent in 198998 control chromosomes (gnomAD). c.389G>C has been reported in the literature in individuals affected with X-linked Chronic Granulomatous Disease (Eguchi_2019, Wu_2017, Roos_2010). At-least one of these reports included CGD patients who fulfilled diagnostic criteria for primary immunodeficiency set by the Pan-American Group for Immunodeficiency (PAGID) and European Society for Immunodeficiencies. These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact of the variant indicated that it promotes skipping of exon 5 resulting in an aberrant transcript (Eguchi_2019) consistent with the computational predictions. Moreover, a different study mentioned undetectable gp91-phox protein levels as a result of the variant occurrence without however providing evidence for independent assessment (Roos_2010). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 130 of the CYBB protein (p.Arg130Pro). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with chronic granulomatous disease (PMID: 20729109, 28251166, 30633606; internal data). ClinVar contains an entry for this variant (Variation ID: 35972). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CYBB protein function with a negative predictive value of 80%. Studies have shown that this missense change results in skipping of exon 5, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 30633606). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at