rs1556464554

chrX-37782119-TTGTC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000397.4(CYBB):c.80_83del(p.Val27GlyfsTer33) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB NM_000397.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 137 pathogenic variants in the truncated region.
• PP5: Variant X-37782119-TTGTC-T is Pathogenic according to our data. Variant chrX-37782119-TTGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 495863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37782119-TTGTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.80_83del	p.Val27GlyfsTer33	frameshift_variant	2/13	ENST00000378588.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.80_83del	p.Val27GlyfsTer33	frameshift_variant	2/13	1	NM_000397.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 03, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 495863). This variant is also known as 92–95 TCTG. This premature translational stop signal has been observed in individual(s) with clinical features of chronic granulomatous disease (PMID: 11162142, 29560547, 32040803). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val27Glyfs*33) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1556464554; hg19: chrX-37641372;