rs151344463

Positions:

• chrX-37796134-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000397.4(CYBB):​c.667G>T​(p.Gly223Ter) variant causes a stop gained change involving the alteration of a 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 not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB NM_000397.4 stop_gained
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.60

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYBB	NM_000397.4	c.667G>T	p.Gly223Ter	stop_gained	6/13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.361G>T	p.Gly121Ter	stop_gained	5/12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.667G>T	p.Gly223Ter	stop_gained	6/13	1	NM_000397.4	ENSP00000367851	P1
CYBB	ENST00000696171.1	c.571G>T	p.Gly191Ter	stop_gained	5/12			ENSP00000512462
CYBB	ENST00000696170.1	c.*176G>T		3_prime_UTR_variant, NMD_transcript_variant	5/12			ENSP00000512461
CYBB	ENST00000696172.1	c.338-2821G>T		intron_variant, NMD_transcript_variant				ENSP00000512463

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.98
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs151344463; hg19: chrX-37655387; COSMIC: COSV101059850; COSMIC: COSV101059850;