chrX-37796093-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM2PM5PP3_StrongPP5_Very_Strong

The NM_000397.4(CYBB):​c.626A>G​(p.His209Arg) variant causes a missense 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H209Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

CYBB
NM_000397.4 missense

Scores

15
1
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 8.95
Variant links:
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.

PS1
Transcript NM_000397.4 (CYBB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant X-37796093-A-G is Pathogenic according to our data. Variant chrX-37796093-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37796093-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYBBNM_000397.4 linkc.626A>G p.His209Arg missense_variant 6/13 ENST00000378588.5 NP_000388.2 P04839A0A0S2Z3S6
CYBBXM_047441855.1 linkc.320A>G p.His107Arg missense_variant 5/12 XP_047297811.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYBBENST00000378588.5 linkc.626A>G p.His209Arg missense_variant 6/131 NM_000397.4 ENSP00000367851.4 P04839
ENSG00000250349ENST00000465127.1 linkc.171+370093A>G intron_variant 5 ENSP00000417050.1 B4E171

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 24, 2017The H209R variant in the CYBB gene has been published previously in association with chronic granulomatous disease (CGD) (Ishibashi et al., 2000; Kojima et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016). The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position within the ferric oxidoreductase domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies on the H209C and H209Y variants have indicated that the H209 residue is critical for heme binding and maturation of flavocytochrome b (Biberstine-Kinkade et al., 2001). Therefore, this variant is likely pathogenic. -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Granulomatous disease, chronic, X-linked Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant p.H209R in CYBB (NM_000397.4) gene has been published previously in association with chronic granulomatous disease (CGD) (Ishibashi et al., 2000). Functional studies indicate a damaging effect (Biberstine-Kinkade et al., 2001). The variant has been submitted to ClinVar as Likely Pathogenic.The p.H209R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The histidine residue at codon 209 of CYBB is conserved in all mammalian species. The nucleotide c.626 in CYBB is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.83
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-7.5
D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.97
Gain of MoRF binding (P = 0.0521);
MVP
1.0
MPC
1.8
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.98
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs151344482; hg19: chrX-37655346; API