rs151344484

Positions:

• chrX-37803991-C-T

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.1012C>T​(p.His338Tyr) 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. H338Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.57

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 binding_site (size 6) in uniprot entity CY24B_HUMAN there are 6 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 chrX-37803993-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2135668.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-37803991-C-T is Pathogenic according to our data. Variant chrX-37803991-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68367.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-37803991-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.1012C>T	p.His338Tyr	missense_variant	9/13	ENST00000378588.5
CYBB	XM_047441855.1	c.706C>T	p.His236Tyr	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.1012C>T	p.His338Tyr	missense_variant	9/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.916C>T	p.His306Tyr	missense_variant	8/12
CYBB	ENST00000492288.1	n.437C>T		non_coding_transcript_exon_variant	4/4	3
CYBB	ENST00000696170.1	c.*521C>T		3_prime_UTR_variant, NMD_transcript_variant	8/12

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2020

This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with chronic granulomatous disease (PMID: 8634410, 9774399, 29560547, 22924696). This variant is also known as C1024T in the literature and the CYBB gene is alternatively known as gp91phox or NOX2. ClinVar contains an entry for this variant (Variation ID: 68367). This variant has been reported to affect CYBB protein function (PMID: 25252997). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces histidine with tyrosine at codon 338 of the CYBB protein (p.His338Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -

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	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	1.0
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.99		Loss of disorder (P = 0.1124);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
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: rs151344484; hg19: chrX-37663244;