rs193922449
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000397.4(CYBB):c.607G>T(p.Glu203Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Consequence
CYBB
NM_000397.4 stop_gained
NM_000397.4 stop_gained
Scores
3
1
1
Clinical Significance
Conservation
PhyloP100: 9.60
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.
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-37796074-G-T is Pathogenic according to our data. Variant chrX-37796074-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35974.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.607G>T | p.Glu203Ter | stop_gained | 6/13 | ENST00000378588.5 | |
CYBB | XM_047441855.1 | c.301G>T | p.Glu101Ter | stop_gained | 5/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.607G>T | p.Glu203Ter | stop_gained | 6/13 | 1 | NM_000397.4 | P1 | |
CYBB | ENST00000696171.1 | c.511G>T | p.Glu171Ter | stop_gained | 5/12 | ||||
CYBB | ENST00000696170.1 | c.*116G>T | 3_prime_UTR_variant, NMD_transcript_variant | 5/12 | |||||
CYBB | ENST00000696172.1 | c.338-2881G>T | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Granulomatous disease, chronic, X-linked Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2018 | This sequence change creates a premature translational stop signal (p.Glu203*) in the CYBB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with chronic granulomatous disease (PMID: 8634410, 20729109). ClinVar contains an entry for this variant (Variation ID: 35974). Loss-of-function variants in CYBB are known to be pathogenic (PMID: 9585602, 20729109). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;D
Vest4
GERP RS
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