rs151344492

Positions:

• chrX-37810841-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000397.4(CYBB):​c.1637T>C​(p.Leu546Pro) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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, 0.994
• PP5: Variant X-37810841-T-C is Pathogenic according to our data. Variant chrX-37810841-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68389.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}. Variant chrX-37810841-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.1637T>C	p.Leu546Pro	missense_variant	13/13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.1331T>C	p.Leu444Pro	missense_variant	12/12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.1637T>C	p.Leu546Pro	missense_variant	13/13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+384841T>C		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2024	Published functional studies demonstrate a damaging effect: p.(L546P) significantly reduces oxidase and diaphorase activity and inhibits phox translocation (PMID: 20724480); 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: 35796921, 21604087, 20724480, 34175765, 10089913) -

Granulomatous disease, chronic, X-linked Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Leu546 amino acid residue in CYBB. Other variant(s) that disrupt this residue have been observed in individuals with CYBB-related conditions (PMID: 10089913, 21604087), which suggests that this may be a clinically significant amino acid residue. 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: 68389). This missense change has been observed in individual(s) with chronic granulomatous disease (PMID: 10089913). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 546 of the CYBB protein (p.Leu546Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.96		Gain of disorder (P = 0.0185);
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		1.0
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: rs151344492; hg19: chrX-37670094;