rs151344466

chrX-37803904-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000397.4(CYBB):c.925G>A(p.Glu309Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,587 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.60

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 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000397.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-37803904-G-A is Pathogenic according to our data. Variant chrX-37803904-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37803904-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.925G>A	p.Glu309Lys	missense_variant	9/13	ENST00000378588.5
CYBB	XM_047441855.1	c.619G>A	p.Glu207Lys	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.925G>A	p.Glu309Lys	missense_variant	9/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.829G>A	p.Glu277Lys	missense_variant	8/12
CYBB	ENST00000492288.1	n.350G>A		non_coding_transcript_exon_variant	4/4	3
CYBB	ENST00000696170.1	c.*434G>A		3_prime_UTR_variant, NMD_transcript_variant	8/12

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096587 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362217

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

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:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYBB function (PMID: 25252997). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYBB protein function. ClinVar contains an entry for this variant (Variation ID: 68412). This missense change has been observed in individuals with chronic granulomatous disease (PMID: 8634410, 9585602, 10068684, 20729109, 30470980). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the CYBB protein (p.Glu309Lys). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2023	Variant summary: CYBB c.925G>A (p.Glu309Lys) results in a conservative amino acid change located in the FAD-binding 8 domain (IPR013112) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182189 control chromosomes. c.925G>A has been reported in the literature in multiple individuals affected with X-Linked Chronic Granulomatous Disease (e.g., Di Matteo_2009, Kuhns_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. X-CGD mutant PLB-985 cells with this variant demonstrated only faint residual NADPH oxidase activity compared to WT (e.g., Beaumel_2014). The following publications have been ascertained in the context of this evaluation (PMID: 25252997, 19410294, 21190454). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with chronic granulomatous disease (MIM#306400) and mycobacteriosis immunodeficiency 34 (MIM#300645). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a minor amino acid change. 0600 - Variant is located in the annotated FAD binding 8 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by one clinical diagnostic laboratory and has been reported in multiple male individuals with chronic granulomatous disease. Additionally, their mothers were confirmed as carriers of the variant (ClinVar; PMIDs: 19410294, 26185101, 30470980, 31456102, 33963972). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been identified in four affected male individuals within the same family (PMID: 19410294). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.84		Gain of MoRF binding (P = 0.0044);
MVP		1.0
MPC		1.7
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151344466; hg19: chrX-37663157;