rs151344454

Positions:

• chrX-37810813-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000378588.5(CYBB):​c.1609T>C​(p.Cys537Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C537F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB ENST00000378588.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.14

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 18 ACMG points.

• PM1: In a strand (size 7) in uniprot entity CY24B_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000378588.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-37810814-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2128256.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-37810813-T-C is Pathogenic according to our data. Variant chrX-37810813-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 68386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37810813-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYBB	NM_000397.4	c.1609T>C	p.Cys537Arg	missense_variant	13/13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.1303T>C	p.Cys435Arg	missense_variant	12/12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.1609T>C	p.Cys537Arg	missense_variant	13/13	1	NM_000397.4	ENSP00000367851	P1
CYBB	ENST00000696171.1	c.1513T>C	p.Cys505Arg	missense_variant	12/12			ENSP00000512462
CYBB	ENST00000696170.1	c.*1118T>C		3_prime_UTR_variant, NMD_transcript_variant	12/12			ENSP00000512461

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

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	Mar 30, 2017	Variant summary: The CYBB c.1609T>C (p.Cys537Arg) variant located in the NADPH binding domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. Multiple functional studies, Jirapongsananuruk_2003, de Oliveria-Junior_2012, and Desbeurme_2010 indicate that the variant has a pathogenic effect on the protein, imparticular causing no detectable NADPH oxidase activity. The variant of interest was not observed in 86762 control chromosomes (ExAC) and multiple publications have cited the variant in affected individuals. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2018	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CYBB protein function (PMID: 20724480). This variant has been observed in several individuals affected with X-linked chronic granulomatous disease (PMID: 22540226, 28168067, 12589359, 9585602). This variant is also referred to as c.1621T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 68386). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 537 of the CYBB protein (p.Cys537Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2023	Published functional studies demonstrate the variant nearly abolishes NADPH oxidase activity and leads to steric conflicts likely incompatible with NADPH orientation (Debeurme et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21190454, 12139950, 12589359, 26210446, 9585602, 20729109, 29560547, 34175765, 31172472, 35796921, 28168067, 22540226, 30506560, 20724480) -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.99		Gain of disorder (P = 0.0276);
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs151344454; hg19: chrX-37670066;