rs151344483

chrX-37796138-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate

The NM_000397.4(CYBB):c.671C>G(p.Ala224Gly) variant causes a missense 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 not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A224S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.243

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 Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_000397.4 (CYBB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000397.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.671C>G	p.Ala224Gly	missense_variant	6/13	ENST00000378588.5
CYBB	XM_047441855.1	c.365C>G	p.Ala122Gly	missense_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.671C>G	p.Ala224Gly	missense_variant	6/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.575C>G	p.Ala192Gly	missense_variant	5/12
CYBB	ENST00000696170.1	c.*180C>G		3_prime_UTR_variant, NMD_transcript_variant	5/12
CYBB	ENST00000696172.1	c.338-2817C>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

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
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	23
Dann	Benign	0.90
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.67
Sift	Benign	0.34	T
Sift4G	Benign	0.33	T
Polyphen		0.41	B
Vest4		0.82
MutPred		0.80		Gain of loop (P = 0.0312);
MVP		1.0
MPC		0.63
ClinPred		0.39	T
GERP RS		3.7
Varity_R		0.52
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: -1
DS_DL_spliceai		0.76		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs151344483; hg19: chrX-37655391;