dbSNP rs137854592: CYBB:p.Arg226Gly (chrX-37798956-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000397.4(CYBB):c.676C>G(p.Arg226Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,091,613 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

CYBB
NM_000397.4 missense, splice_region

Scores

Splicing: ADA: 0.0006942

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

Publications

0 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 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_000397.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4 link	c.676C>G	p.Arg226Gly	missense_variant, splice_region_variant	Exon 7 of 13	ENST00000378588.5	NP_000388.2	P04839A0A0S2Z3S6
CYBB	XM_047441855.1 link	c.370C>G	p.Arg124Gly	missense_variant, splice_region_variant	Exon 6 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5 link	c.676C>G	p.Arg226Gly	missense_variant, splice_region_variant	Exon 7 of 13	1	NM_000397.4	ENSP00000367851.4		P04839
ENSG00000250349	ENST00000465127.1 link	c.171+372956C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000366

AC:

AN:

1091613

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

358473

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26176

American (AMR)

AF:

0.00

AC:

AN:

34848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19240

East Asian (EAS)

AF:

0.00

AC:

AN:

29941

South Asian (SAS)

AF:

0.00

AC:

AN:

53574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00000478

AC:

AN:

837657

Other (OTH)

AF:

0.00

AC:

AN:

45773

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.80

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.2

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.040

REVEL

Uncertain

0.56

Sift

Benign

0.57

Sift4G

Benign

0.31

Polyphen

0.051

Vest4

0.59

MutPred

0.46

Loss of helix (P = 0.0376);

MVP

1.0

MPC

0.77

ClinPred

0.30

GERP RS

3.1

Varity_R

0.23

gMVP

0.96

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00069

dbscSNV1_RF

Benign

0.082

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over