rs886041194

Variant names:

• chrX-37799016-C-CA
• rs886041194
• NM_000397.4:c.742dupA

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.742dupA​(p.Ile248AsnfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.86

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-37799016-C-CA is Pathogenic according to our data. Variant chrX-37799016-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 279796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.742dupA	p.Ile248AsnfsTer36	frameshift_variant	Exon 7 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.436dupA	p.Ile146AsnfsTer36	frameshift_variant	Exon 6 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.742dupA	p.Ile248AsnfsTer36	frameshift_variant	Exon 7 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+373022dupA		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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:2

May 10, 2024

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.742dupA (p.Ile248AsnfsX36) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 181863 control chromosomes. c.742dupA has been reported in the literature in individuals affected with X-Linked Chronic Granulomatous Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 18546332). ClinVar contains an entry for this variant (Variation ID: 279796). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ile248Asnfs*36) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with chronic granulomatous disease (PMID: 8634410, 18546332, 27701760). ClinVar contains an entry for this variant (Variation ID: 279796). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Aug 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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: 32089701, 24999735, 20729109, 8916969, 9585602, 25897114, 35140711, 22929960, 7525551, 9454688, 11162142, 10914676, 24401677, 8634410, 24869932, 23288160, 27701760, 18546332, 29560547, 32040803, 33717137, 35874699) -

Computational scores

Source: dbNSFP v4.3

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: rs886041194; hg19: chrX-37658269;