rs28935181

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000397.4(CYBB):​c.1499A>G​(p.Asp500Gly) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D500E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

CYBB
NM_000397.4 missense

Scores

11
5
1

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 287) in uniprot entity CY24B_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000397.4
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, 0.99
PP5
Variant X-37809604-A-G is Pathogenic according to our data. Variant chrX-37809604-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10931.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-37809604-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYBBNM_000397.4 linkuse as main transcriptc.1499A>G p.Asp500Gly missense_variant 12/13 ENST00000378588.5 NP_000388.2 P04839A0A0S2Z3S6
CYBBXM_047441855.1 linkuse as main transcriptc.1193A>G p.Asp398Gly missense_variant 11/12 XP_047297811.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYBBENST00000378588.5 linkuse as main transcriptc.1499A>G p.Asp500Gly missense_variant 12/131 NM_000397.4 ENSP00000367851.4 P04839
ENSG00000250349ENST00000465127.1 linkuse as main transcriptc.171+383604A>G intron_variant 5 ENSP00000417050.1 B4E171

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 1994- -
not provided Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.82
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-6.7
D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.67
MutPred
0.96
Gain of sheet (P = 0.0827);
MVP
1.0
MPC
1.8
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.98
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs137854593; hg19: chrX-37668857; API