rs151344466
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000397.4(CYBB):c.925G>A(p.Glu309Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,587 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 Pathogenic (★★).
Frequency
Consequence
NM_000397.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYBB | NM_000397.4 | c.925G>A | p.Glu309Lys | missense_variant | 9/13 | ENST00000378588.5 | |
CYBB | XM_047441855.1 | c.619G>A | p.Glu207Lys | missense_variant | 8/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYBB | ENST00000378588.5 | c.925G>A | p.Glu309Lys | missense_variant | 9/13 | 1 | NM_000397.4 | P1 | |
CYBB | ENST00000696171.1 | c.829G>A | p.Glu277Lys | missense_variant | 8/12 | ||||
CYBB | ENST00000492288.1 | n.350G>A | non_coding_transcript_exon_variant | 4/4 | 3 | ||||
CYBB | ENST00000696170.1 | c.*434G>A | 3_prime_UTR_variant, NMD_transcript_variant | 8/12 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome AF: 9.12e-7 AC: 1AN: 1096587Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 362217
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Granulomatous disease, chronic, X-linked Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYBB function (PMID: 25252997). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYBB protein function. ClinVar contains an entry for this variant (Variation ID: 68412). This missense change has been observed in individuals with chronic granulomatous disease (PMID: 8634410, 9585602, 10068684, 20729109, 30470980). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the CYBB protein (p.Glu309Lys). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2023 | Variant summary: CYBB c.925G>A (p.Glu309Lys) results in a conservative amino acid change located in the FAD-binding 8 domain (IPR013112) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182189 control chromosomes. c.925G>A has been reported in the literature in multiple individuals affected with X-Linked Chronic Granulomatous Disease (e.g., Di Matteo_2009, Kuhns_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. X-CGD mutant PLB-985 cells with this variant demonstrated only faint residual NADPH oxidase activity compared to WT (e.g., Beaumel_2014). The following publications have been ascertained in the context of this evaluation (PMID: 25252997, 19410294, 21190454). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with chronic granulomatous disease (MIM#306400) and mycobacteriosis immunodeficiency 34 (MIM#300645). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a minor amino acid change. 0600 - Variant is located in the annotated FAD binding 8 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by one clinical diagnostic laboratory and has been reported in multiple male individuals with chronic granulomatous disease. Additionally, their mothers were confirmed as carriers of the variant (ClinVar; PMIDs: 19410294, 26185101, 30470980, 31456102, 33963972). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been identified in four affected male individuals within the same family (PMID: 19410294). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at