rs151344452

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000397.4(CYBB):c.1551T>A(p.Asp517Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,207,338 control chromosomes in the GnomAD database, including 4 homozygotes. There are 776 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., 42 hem., cov: 23)

Exomes 𝑓: 0.0022 ( 3 hom. 734 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 1.26

Publications

7 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000397.4

BP4

Computational evidence support a benign effect (MetaRNN=0.018161982).

BP6

Variant X-37809656-T-A is Benign according to our data. Variant chrX-37809656-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (156/111849) while in subpopulation NFE AF = 0.00252 (134/53122). AF 95% confidence interval is 0.00217. There are 1 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 42 XL,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4 link	c.1551T>A	p.Asp517Glu	missense_variant	Exon 12 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1 link	c.1245T>A	p.Asp415Glu	missense_variant	Exon 11 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5 link	c.1551T>A	p.Asp517Glu	missense_variant	Exon 12 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1 link	c.171+383656T>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

155

AN:

111796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000762

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.000164

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00252

Gnomad OTH

AF:

0.000666

GnomAD2 exomes

AF:

0.00118

AC:

209

AN:

176958

AF XY:

0.00108

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.000446

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000193

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.00215

AC:

2360

AN:

1095489

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

734

AN XY:

361337

show subpopulations

African (AFR)

AF:

0.000228

AC:

AN:

26354

American (AMR)

AF:

0.000400

AC:

AN:

34998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19316

East Asian (EAS)

AF:

0.00

AC:

AN:

30167

South Asian (SAS)

AF:

0.00105

AC:

AN:

53512

European-Finnish (FIN)

AF:

0.000272

AC:

AN:

40378

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00263

AC:

2208

AN:

840637

Other (OTH)

AF:

0.00137

AC:

AN:

45994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

177

265

354

442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.00139

AC:

156

AN:

111849

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

34051

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30818

American (AMR)

AF:

0.000761

AC:

AN:

10507

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.000281

AC:

AN:

3558

South Asian (SAS)

AF:

0.00150

AC:

AN:

2672

European-Finnish (FIN)

AF:

0.000164

AC:

AN:

6094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00252

AC:

134

AN:

53122

Other (OTH)

AF:

0.000658

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.00120

Hom.:

Bravo

AF:

0.00113

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00242

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00134

AC:

162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 02, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 04, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CYBB c.1551T>A (p.Asp517Glu) results in a conservative amino acid change located in the Ferric reductase, NAD binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 193905 control chromosomes, including 75 hemizygous males, predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CYBB causing X-linked Chronic Granulomatous Disease phenotype (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.1551T>A, has been reported in the literature in one individual affected with X-linked Chronic Granulomatous Disease as a benign variant, together with c.90C>A (p.Y30X)(Hill_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Granulomatous disease, chronic, X-linked

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CYBB-related disorder

Benign:1

Sep 22, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.018

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.72

PhyloP100

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.31

Sift

Benign

0.23

Sift4G

Benign

0.21

Polyphen

0.0040

Vest4

0.048

MutPred

0.17

Loss of loop (P = 0.0804);

MVP

0.92

MPC

0.57

ClinPred

0.016

GERP RS

3.3

Varity_R

0.35

gMVP

0.74

Mutation Taster

=78/21

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over