rs886041194
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000397.4(CYBB):c.742dup(p.Ile248AsnfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
CYBB
NM_000397.4 frameshift
NM_000397.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.86
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-37799016-C-CA is Pathogenic according to our data. Variant chrX-37799016-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 279796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYBB | NM_000397.4 | c.742dup | p.Ile248AsnfsTer36 | frameshift_variant | 7/13 | ENST00000378588.5 | |
CYBB | XM_047441855.1 | c.436dup | p.Ile146AsnfsTer36 | frameshift_variant | 6/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.742dup | p.Ile248AsnfsTer36 | frameshift_variant | 7/13 | 1 | NM_000397.4 | P1 |
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32089701, 24999735, 20729109, 8916969, 9585602, 25897114, 35140711, 22929960, 7525551, 9454688, 11162142, 10914676, 24401677, 8634410, 24869932, 23288160, 27701760, 18546332, 29560547, 32040803, 33717137, 35874699) - |
Granulomatous disease, chronic, X-linked Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 28, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279796). This premature translational stop signal has been observed in individual(s) with chronic granulomatous disease (PMID: 8634410, 18546332, 27701760). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile248Asnfs*36) in the CYBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYBB are known to be pathogenic (PMID: 9585602, 20729109). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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