rs137854588

Variant names:

• chrX-37783565-C-T
• rs137854588
• NM_000397.4:c.217C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000397.4(CYBB):​c.217C>T​(p.Arg73*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB NM_000397.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.90

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 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-37783565-C-T is Pathogenic according to our data. Variant chrX-37783565-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37783565-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.217C>T	p.Arg73*	stop_gained	Exon 3 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.-214C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12		XP_047297811.1
CYBB	XM_047441855.1	c.-214C>T		5_prime_UTR_variant	Exon 1 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.217C>T	p.Arg73*	stop_gained	Exon 3 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+357565C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11462241, 28153086, 35140711, 25525159, 1710153, 26453586, 29560547, 30470980, 31594065, 31269551, 32040803, 33365035, 33717137, 35728702, 35874699) -

Sep 12, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Granulomatous disease, chronic, X-linked Pathogenic:2

Jun 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 11, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CYBB are known to be pathogenic (PMID: 9585602, 20729109). This variant has been reported in individuals affected with X-linked chronic granulomatous disease (PMID: 1710153, 11462241, 24999735, 26453586, 20729109). ClinVar contains an entry for this variant (Variation ID: 10923). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg73*) in the CYBB gene. It is expected to result in an absent or disrupted protein product. -

CYBB-related disorder Pathogenic:1

Aug 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CYBB c.217C>T variant is predicted to result in premature protein termination (p.Arg73*). This variant has been reported in individual with X-linked chronic granulomatous disease (Bolscher et al. 1991. PubMed ID: 1710153; Roos et al. 2010. PubMed ID: 20729109; Chan et al. 2022. PubMed ID: 35874699). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CYBB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.72	D
Vest4		0.92
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854588; hg19: chrX-37642818; COSMIC: COSV66086104;