rs193922448
Positions:
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 (★★). Synonymous variant affecting the same amino acid position (i.e. R130R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 21)
Consequence
CYBB
NM_000397.4 missense
NM_000397.4 missense
Scores
6
5
6
Clinical Significance
Conservation
PhyloP100: 3.65
Genes affected
CYBB (HGNC:2578): (cytochrome b-245 beta chain) Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a domain Ferric oxidoreductase (size 232) in uniprot entity CY24B_HUMAN there are 37 pathogenic changes around while only 12 benign (76%) in NM_000397.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.92
PP5
?
Variant X-37793716-G-C is Pathogenic according to our data. Variant chrX-37793716-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 35972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37793716-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYBB | NM_000397.4 | c.389G>C | p.Arg130Pro | missense_variant | 5/13 | ENST00000378588.5 | |
CYBB | XM_047441855.1 | c.83G>C | p.Arg28Pro | missense_variant | 4/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.389G>C | p.Arg130Pro | missense_variant | 5/13 | 1 | NM_000397.4 | P1 | |
CYBB | ENST00000696171.1 | c.293G>C | p.Arg98Pro | missense_variant | 4/12 | ||||
CYBB | ENST00000696170.1 | c.337+1657G>C | intron_variant, NMD_transcript_variant | ||||||
CYBB | ENST00000696172.1 | c.337+1657G>C | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 21
GnomAD3 genomes
?
Cov.:
21
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 21
GnomAD4 genome
?
Cov.:
21
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Granulomatous disease, chronic, X-linked Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2021 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with skipping of exon 5, which introduces a premature termination codon (PMID: 30633606). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with chronic granulomatous disease (PMID: 30633606, 28251166, 20729109, Invitae). ClinVar contains an entry for this variant (Variation ID: 35972). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 130 of the CYBB protein (p.Arg130Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2019 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of stability (P = 0.019);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at