dbSNP rs139670417: CYBB:p.Arg229His (chrX-37798966-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 3P and 14B. PM1PP3BP4_StrongBP6_ModerateBS1BS2

The NM_000397.4(CYBB):c.686G>A(p.Arg229His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,205,587 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., 34 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 48 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 9.56

Publications

2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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 -11 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000397.4

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.032025635).

BP6

Variant X-37798966-G-A is Benign according to our data. Variant chrX-37798966-G-A is described in ClinVar as Benign. ClinVar VariationId is 533561.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00103 (115/111852) while in subpopulation AFR AF = 0.00353 (109/30839). AF 95% confidence interval is 0.003. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 34 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	NM_000397.4	MANE Select	c.686G>A	p.Arg229His	missense	Exon 7 of 13	NP_000388.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYBB	ENST00000378588.5	TSL:1 MANE Select	c.686G>A	p.Arg229His	missense	Exon 7 of 13	ENSP00000367851.4	P04839
ENSG00000250349	ENST00000465127.1	TSL:5	c.171+372966G>A		intron	N/A	ENSP00000417050.1	B4E171
CYBB	ENST00000968558.1		c.686G>A	p.Arg229His	missense	Exon 7 of 14	ENSP00000638617.1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

115

AN:

111801

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00354

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000569

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000346

AC:

AN:

176325

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.00331

Gnomad AMR exome

AF:

0.000297

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000258

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.000166

AC:

182

AN:

1093735

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

360155

show subpopulations

African (AFR)

AF:

0.00411

AC:

108

AN:

26252

American (AMR)

AF:

0.000315

AC:

AN:

34965

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

19281

East Asian (EAS)

AF:

0.0000666

AC:

AN:

30023

South Asian (SAS)

AF:

0.00

AC:

AN:

53768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.0000334

AC:

AN:

839080

Other (OTH)

AF:

0.000218

AC:

AN:

45864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

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:

0.00103

AC:

115

AN:

111852

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

AN XY:

34144

show subpopulations

African (AFR)

AF:

0.00353

AC:

109

AN:

30839

American (AMR)

AF:

0.000569

AC:

AN:

10552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3530

South Asian (SAS)

AF:

0.00

AC:

AN:

2731

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53079

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000508

Hom.:

Bravo

AF:

0.00131

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000512

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Chronic granulomatous disease (1)

CYBB-related disorder (1)

Granulomatous disease, chronic, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.68

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.032

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

PhyloP100

9.6

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.60

MVP

1.0

MPC

0.96

ClinPred

0.66

GERP RS

5.2

Varity_R

0.78

gMVP

0.84

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Computational scores

Splicing

Publications

Other links and lift over