rs193922448

chrX-37793716-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000397.4(CYBB):c.389G>C(p.Arg130Pro) variant causes a missense change. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R130R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain Ferric oxidoreductase (size 232) in uniprot entity CY24B_HUMAN there are 37 pathogenic changes around while only 12 benign (76%) in NM_000397.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant X-37793716-G-C is Pathogenic according to our data. Variant chrX-37793716-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 35972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37793716-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.389G>C	p.Arg130Pro	missense_variant	5/13	ENST00000378588.5
CYBB	XM_047441855.1	c.83G>C	p.Arg28Pro	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.389G>C	p.Arg130Pro	missense_variant	5/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.293G>C	p.Arg98Pro	missense_variant	4/12
CYBB	ENST00000696170.1	c.337+1657G>C		intron_variant, NMD_transcript_variant
CYBB	ENST00000696172.1	c.337+1657G>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2019	Variant summary: CYBB c.389G>C (p.Arg130Pro) results in a non-conservative amino acid change located in the Ferric reductase transmembrane component-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. One out of 3 computational tools predict a significant impact on normal splicing, namely a disruption of the binding site for the SRSF6 (SRp55) splicing factor within the splicing-regulatory sequence in exon 5 of the CYBB gene. The variant was absent in 198998 control chromosomes (gnomAD). c.389G>C has been reported in the literature in individuals affected with X-linked Chronic Granulomatous Disease (Eguchi_2019, Wu_2017, Roos_2010). At-least one of these reports included CGD patients who fulfilled diagnostic criteria for primary immunodeficiency set by the Pan-American Group for Immunodeficiency (PAGID) and European Society for Immunodeficiencies. These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact of the variant indicated that it promotes skipping of exon 5 resulting in an aberrant transcript (Eguchi_2019) consistent with the computational predictions. Moreover, a different study mentioned undetectable gp91-phox protein levels as a result of the variant occurrence without however providing evidence for independent assessment (Roos_2010). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2021	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with skipping of exon 5, which introduces a premature termination codon (PMID: 30633606). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with chronic granulomatous disease (PMID: 30633606, 28251166, 20729109, Invitae). ClinVar contains an entry for this variant (Variation ID: 35972). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 130 of the CYBB protein (p.Arg130Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.75
Sift	Benign	0.068	T
Sift4G	Benign	0.090	T
Polyphen		0.93	P
Vest4		0.81
MutPred		0.65		Loss of stability (P = 0.019);
MVP		1.0
MPC		0.89
ClinPred		0.85	D
GERP RS		3.7
Varity_R		0.70
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs193922448; hg19: chrX-37652969;