rs137854592

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000397.4(CYBB):c.676C>T(p.Arg226Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,757 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CYBB
NM_000397.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.1092

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.11

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-37798956-C-T is Pathogenic according to our data. Variant chrX-37798956-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37798956-C-T is described in Lovd as [Pathogenic]. Variant chrX-37798956-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4 linkuse as main transcript	c.676C>T	p.Arg226Ter	stop_gained, splice_region_variant	7/13	ENST00000378588.5
CYBB	XM_047441855.1 linkuse as main transcript	c.370C>T	p.Arg124Ter	stop_gained, splice_region_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5 linkuse as main transcript	c.676C>T	p.Arg226Ter	stop_gained, splice_region_variant	7/13	1	NM_000397.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111757

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34033

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000578

AC:

AN:

173035

Hom.:

AF XY:

0.00

AC XY:

AN XY:

58995

show subpopulations

Gnomad AFR exome

AF:

0.0000801

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1091611

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358473

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111757

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34033

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Granulomatous disease, chronic, X-linked

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2016	Variant summary: The CYBB c.676C>T (p.Arg226X) variant results in a premature termination codon, predicted to cause a truncated or absent CYBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals. In addition, a reputable database cites the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jun 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change creates a premature translational stop signal (p.Arg226*) in the CYBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYBB are known to be pathogenic (PMID: 9585602, 20729109). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with X-linked chronic granulomatous disease (PMID: 1347621, 18546332, 20729109, 23859418, 29560547). ClinVar contains an entry for this variant (Variation ID: 10929). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Published functional studies demonstrated lack of protein expression in neutrophil cells of affected individuals with the p.(R226X) variant (Sun et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 8634410, 1347621, 23859418, 25525159, 10914676, 16569599, 11162142, 9585602, 18546332, 20729109, 24999735, 28153086, 28577521, 28006982, 29560547, 21190454, 30290665, 30470980, 7949143, 31522453, 32040803, 32954498, 34134972, 33717137, 22924737) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2017	The CYBB c.676C>T, p.Arg226Ter variant is reported in the medical literature in multiple individuals diagnosed with X-linked chronic granulomatous disease (CGD) (Curnette 1992, Roos 1996, Rae 1998, Ishibashi 2000, Heyworth 2001, Gerard 2001, von Goessel 2006, Kannengiesser 2008), and listed as pathogenic in CYBB variant database (CYBBbase) (Roos 2010). Functional characterization indicates that the variant leads to the loss of NAPDH-oxidase activity (Curnette 1992, von Goessel 2006, Kannengiesser 2008), resulting in functionally defective neurophils (Kannengiesser 2008). The variant is listed in the ClinVar database (Variation ID: 10929) and the dbSNP variant database (rs137854592). It is not observed in the general population databases, such as the 1000 Genomes Project, the Exome Variant Server, and the Exome Aggregation Consortium (ExAC). The variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Based on the above information, this variant is classified as pathogenic. References: Curnutte J et al. Studying X inactivation. Lancet. 1992 339(8795):749. Gerard B et al. Characterization of 11 novel mutations in the X-linked chronic granulomatous disease (CYBB gene). Hum Mutat. 2001 18(2):163. Heyworth P et al. Hematologically important mutations: X-linked chronic granulomatous disease (second update). Blood Cells Mol Dis. 2001 27(1):16-26. Ishibashi F et al. Statistical and mutational analysis of chronic granulomatous disease in Japan with special reference to gp91-phox and p22-phox deficiency. Hum Genet. 2000 106(5):473-81. Kannengiesser C et al. Molecular epidemiology of chronic granulomatous disease in a series of 80 kindreds: identification of 31 novel mutations. Hum Mutat. 2008 29(9):E132-49. Rae J et al. X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase. Am J Hum Genet.1998 62(6):1320-31. Roos D et al. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis. 2010 45(3):246-65. Roos D et al. Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease. Blood.1996 87(5):1663-81. Von Goessel H et al. Characterization of 17 new cases of X-linked chronic granulomatous disease with seven novel mutations in the CYBB gene. Exp Hematol. 2006 34(4):528-35. -

Chronic granulomatous disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Uncertain

1.0

FATHMM_MKL

Benign

0.46

MutationTaster

Benign

1.0

A;A;A

Vest4

0.96

GERP RS

3.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over