X-37793716-G-C

Variant names:

• chrX-37793716-G-C
• rs193922448
• NM_000397.4:c.389G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000397.4(CYBB):​c.389G>C​(p.Arg130Pro) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R130R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.65
• Publications: 2 publications found

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]

CYBB Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

  Inheritance: XL, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant X-37793716-G-C is Pathogenic according to our data. Variant chrX-37793716-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 35972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000397.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	NM_000397.4	MANE Select	c.389G>C	p.Arg130Pro	missense	Exon 5 of 13	NP_000388.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	ENST00000378588.5	TSL:1 MANE Select	c.389G>C	p.Arg130Pro	missense	Exon 5 of 13	ENSP00000367851.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.171+367716G>C		intron	N/A	ENSP00000417050.1
	CYBB	ENST00000696171.1		c.293G>C	p.Arg98Pro	missense	Exon 4 of 12	ENSP00000512462.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:2

Jan 16, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYBB c.389G>C (p.Arg130Pro) results in a non-conservative amino acid change located in the Ferric reductase transmembrane component-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. One out of 3 computational tools predict a significant impact on normal splicing, namely a disruption of the binding site for the SRSF6 (SRp55) splicing factor within the splicing-regulatory sequence in exon 5 of the CYBB gene. The variant was absent in 198998 control chromosomes (gnomAD). c.389G>C has been reported in the literature in individuals affected with X-linked Chronic Granulomatous Disease (Eguchi_2019, Wu_2017, Roos_2010). At-least one of these reports included CGD patients who fulfilled diagnostic criteria for primary immunodeficiency set by the Pan-American Group for Immunodeficiency (PAGID) and European Society for Immunodeficiencies. These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact of the variant indicated that it promotes skipping of exon 5 resulting in an aberrant transcript (Eguchi_2019) consistent with the computational predictions. Moreover, a different study mentioned undetectable gp91-phox protein levels as a result of the variant occurrence without however providing evidence for independent assessment (Roos_2010). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 130 of the CYBB protein (p.Arg130Pro). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with chronic granulomatous disease (PMID: 20729109, 28251166, 30633606; internal data). ClinVar contains an entry for this variant (Variation ID: 35972). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CYBB protein function with a negative predictive value of 80%. Studies have shown that this missense change results in skipping of exon 5, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 30633606). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.75
Sift	Benign	0.068	T
Sift4G	Benign	0.090	T
Polyphen		0.93	P
Vest4		0.81
MutPred		0.65		Loss of stability (P = 0.019)
MVP		1.0
MPC		0.89
ClinPred		0.85	D
GERP RS		3.7
Varity_R		0.70
gMVP		0.99
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193922448; hg19: chrX-37652969;