rs137854590

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_000397.4(CYBB):c.466G>A(p.Ala156Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000914 in 1,094,487 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A156D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 4.39

Publications

6 publications found

Variant links:

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]

CYBB Gene-Disease associations (from GenCC):

granulomatous disease, chronic, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
chronic granulomatous disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency
Inheritance: XL, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

CYBB links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

PP5

Variant X-37793793-G-A is Pathogenic according to our data. Variant chrX-37793793-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10925.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4 link	c.466G>A	p.Ala156Thr	missense_variant	Exon 5 of 13	ENST00000378588.5	NP_000388.2	P04839A0A0S2Z3S6
CYBB	XM_047441855.1 link	c.160G>A	p.Ala54Thr	missense_variant	Exon 4 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5 link	c.466G>A	p.Ala156Thr	missense_variant	Exon 5 of 13	1	NM_000397.4	ENSP00000367851.4		P04839
ENSG00000250349	ENST00000465127.1 link	c.171+367793G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1094487

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360829

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26293

American (AMR)

AF:

0.00

AC:

AN:

35101

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19311

East Asian (EAS)

AF:

0.00

AC:

AN:

30169

South Asian (SAS)

AF:

0.00

AC:

AN:

54089

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839914

Other (OTH)

AF:

0.00

AC:

AN:

45935

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000430

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Granulomatous disease, chronic, X-linked, variant

Pathogenic:1

Jun 01, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Granulomatous disease, chronic, X-linked

Pathogenic:1

Dec 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 156 of the CYBB protein (p.Ala156Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with chronic granulomatous disease (PMID: 1710153, 20729109, 29560547). ClinVar contains an entry for this variant (Variation ID: 10925). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYBB protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects CYBB function (PMID: 25252997). For these reasons, this variant has been classified as Pathogenic. -

not provided

Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.72

PhyloP100

4.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.15

REVEL

Uncertain

0.50

Sift

Benign

0.25

Sift4G

Benign

0.26

Polyphen

0.064

Vest4

0.25

MutPred

0.81

Loss of helix (P = 0.0196);

MVP

1.0

MPC

0.63

ClinPred

0.36

GERP RS

5.7

Varity_R

0.25

gMVP

0.83

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over