rs151344478
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000397.4(CYBB):c.1601T>A(p.Val534Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,817 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )
Consequence
CYBB
NM_000397.4 missense
NM_000397.4 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 5.44
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a topological_domain Cytoplasmic (size 287) in uniprot entity CY24B_HUMAN there are 53 pathogenic changes around while only 20 benign (73%) in NM_000397.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.995
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYBB | NM_000397.4 | c.1601T>A | p.Val534Asp | missense_variant | 13/13 | ENST00000378588.5 | |
CYBB | XM_047441855.1 | c.1295T>A | p.Val432Asp | missense_variant | 12/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.1601T>A | p.Val534Asp | missense_variant | 13/13 | 1 | NM_000397.4 | P1 | |
CYBB | ENST00000696171.1 | c.1505T>A | p.Val502Asp | missense_variant | 12/12 | ||||
CYBB | ENST00000696170.1 | c.*1110T>A | 3_prime_UTR_variant, NMD_transcript_variant | 12/12 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome AF: 9.13e-7 AC: 1AN: 1095817Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 361519
GnomAD4 exome
AF:
AC:
1
AN:
1095817
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
361519
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Granulomatous disease, chronic, X-linked Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2015 | - - |
not provided Other:1
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
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.1446);
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