rs13306300

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000397.4(CYBB):c.1414G>A(p.Gly472Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000495 in 1,209,121 control chromosomes in the GnomAD database, including 2 homozygotes. There are 199 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G472G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 15 hem., cov: 22)

Exomes 𝑓: 0.00051 ( 2 hom. 184 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.94

Publications

10 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01174444).

BP6

Variant X-37806486-G-A is Benign according to our data. Variant chrX-37806486-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 732210.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000304 (34/111666) while in subpopulation EAS AF = 0.00935 (33/3530). AF 95% confidence interval is 0.00684. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 15 XL,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000397.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	NM_000397.4	MANE Select	c.1414G>A	p.Gly472Ser	missense	Exon 11 of 13	NP_000388.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYBB	ENST00000378588.5	TSL:1 MANE Select	c.1414G>A	p.Gly472Ser	missense	Exon 11 of 13	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	TSL:5	c.171+380486G>A		intron	N/A	ENSP00000417050.1
CYBB	ENST00000696171.1		c.1318G>A	p.Gly440Ser	missense	Exon 10 of 12	ENSP00000512462.1

Frequencies

GnomAD3 genomes

AF:

0.000305

AC:

AN:

111612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00932

Gnomad SAS

AF:

0.000372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000893

AC:

163

AN:

182459

AF XY:

0.000640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000737

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.000514

AC:

564

AN:

1097455

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

184

AN XY:

362987

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26385

American (AMR)

AF:

0.0000285

AC:

AN:

35124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19366

East Asian (EAS)

AF:

0.0171

AC:

517

AN:

30197

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.0000368

AC:

AN:

841658

Other (OTH)

AF:

0.000261

AC:

AN:

46056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000304

AC:

AN:

111666

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

33876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30752

American (AMR)

AF:

0.00

AC:

AN:

10541

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00935

AC:

AN:

3530

South Asian (SAS)

AF:

0.000373

AC:

AN:

2679

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53068

Other (OTH)

AF:

0.00

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000606

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000807

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Chronic granulomatous disease (1)

CYBB-related disorder (1)

Granulomatous disease, chronic, X-linked (1)

Granulomatous disease, chronic, X-linked;C1970859:X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.81

MetaRNN

Benign

0.012

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.4

PhyloP100

3.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.42

REVEL

Benign

0.21

Sift

Benign

0.090

Sift4G

Benign

0.14

Polyphen

0.097

Vest4

0.056

MVP

0.86

MPC

0.65

ClinPred

0.020

GERP RS

3.8

Varity_R

0.22

gMVP

0.59

Mutation Taster

=71/29

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over