rs151344454
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000378588.5(CYBB):c.1609T>C(p.Cys537Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C537F) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 23)
Consequence
CYBB
ENST00000378588.5 missense
ENST00000378588.5 missense
Scores
15
1
1
Clinical Significance
Conservation
PhyloP100: 7.14
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 18 ACMG points.
PM1
In a strand (size 7) in uniprot entity CY24B_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000378588.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-37810814-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2128256.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant X-37810813-T-C is Pathogenic according to our data. Variant chrX-37810813-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 68386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37810813-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYBB | NM_000397.4 | c.1609T>C | p.Cys537Arg | missense_variant | 13/13 | ENST00000378588.5 | NP_000388.2 | |
CYBB | XM_047441855.1 | c.1303T>C | p.Cys435Arg | missense_variant | 12/12 | XP_047297811.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.1609T>C | p.Cys537Arg | missense_variant | 13/13 | 1 | NM_000397.4 | ENSP00000367851 | P1 | |
CYBB | ENST00000696171.1 | c.1513T>C | p.Cys505Arg | missense_variant | 12/12 | ENSP00000512462 | ||||
CYBB | ENST00000696170.1 | c.*1118T>C | 3_prime_UTR_variant, NMD_transcript_variant | 12/12 | ENSP00000512461 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2017 | Variant summary: The CYBB c.1609T>C (p.Cys537Arg) variant located in the NADPH binding domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. Multiple functional studies, Jirapongsananuruk_2003, de Oliveria-Junior_2012, and Desbeurme_2010 indicate that the variant has a pathogenic effect on the protein, imparticular causing no detectable NADPH oxidase activity. The variant of interest was not observed in 86762 control chromosomes (ExAC) and multiple publications have cited the variant in affected individuals. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2018 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CYBB protein function (PMID: 20724480). This variant has been observed in several individuals affected with X-linked chronic granulomatous disease (PMID: 22540226, 28168067, 12589359, 9585602). This variant is also referred to as c.1621T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 68386). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 537 of the CYBB protein (p.Cys537Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2023 | Published functional studies demonstrate the variant nearly abolishes NADPH oxidase activity and leads to steric conflicts likely incompatible with NADPH orientation (Debeurme et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21190454, 12139950, 12589359, 26210446, 9585602, 20729109, 29560547, 34175765, 31172472, 35796921, 28168067, 22540226, 30506560, 20724480) - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0276);
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