rs1556473119

Positions:

• chrX-37810906-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000397.4(CYBB):​c.1702G>A​(p.Glu568Lys) 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.92

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 287) in uniprot entity CY24B_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000397.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant X-37810906-G-A is Pathogenic according to our data. Variant chrX-37810906-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 533556.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-37810906-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYBB	NM_000397.4	c.1702G>A	p.Glu568Lys	missense_variant	13/13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.1396G>A	p.Glu466Lys	missense_variant	12/12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.1702G>A	p.Glu568Lys	missense_variant	13/13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+384906G>A		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2019

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change abolishes the NADPH oxidase assembly process (PMID: 10627478, 20724480). This variant has been reported in an individual affected with X-linked chronic granulomatous disease (CGD) (PMID: 10627478). This variant has also been observed to segregate in a single family in which affected members displayed symptoms consistent with CGD in (Invitae). This sequence change replaces glutamic acid with lysine at codon 568 of the CYBB protein (p.Glu568Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.84		Gain of MoRF binding (P = 2e-04);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
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: rs1556473119; hg19: chrX-37670159;