rs137854591

Positions:

• chrX-37792024-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000397.4(CYBB):​c.302A>G​(p.His101Arg) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H101Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 8.72

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 12 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-37792023-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10932.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-37792024-A-G is Pathogenic according to our data. Variant chrX-37792024-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-37792024-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.302A>G	p.His101Arg	missense_variant	4/13	ENST00000378588.5
CYBB	XM_047441855.1	c.-5A>G		5_prime_UTR_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.302A>G	p.His101Arg	missense_variant	4/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.206A>G	p.His69Arg	missense_variant	3/12
CYBB	ENST00000696172.1	c.302A>G	p.His101Arg	missense_variant, NMD_transcript_variant	4/6
CYBB	ENST00000696170.1	c.302A>G	p.His101Arg	missense_variant, NMD_transcript_variant	4/12

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Granulomatous disease, chronic, X-linked, variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1991

- -

Granulomatous disease, chronic, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2019

Variant summary: CYBB c.302A>G (p.His101Arg) results in a non-conservative amino acid change located in the Ferric reductase transmembrane component-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182647 control chromosomes (gnomAD). c.302A>G has been reported in the literature in individuals affected with X-linked Chronic Granulomatous Disease (Bolscher_1991, Roos_1996, Zhou_2018, de Oliveira-Junior_2015). One publication (Bolscher_1991) reports disease in a female patient with apparent X-inactivation of the wild-type chromosome. These data indicate that the variant may be associated with disease. Functional studies investigating a different amino acid change at this codon (p.His101Leu) suggest that this histidine is critical for heme binding and protein function (Biberstine-Kinkade_2001). In addition, another variant, c.301C>T, affecting this same codon, H101Y, has also been reported to be associated with disease (HGMD). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Other:1

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	0.71	D
BayesDel_noAF	Pathogenic	0.79
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.98		Gain of MoRF binding (P = 0.017);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		1.0

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: rs137854591; hg19: chrX-37651277;