rs35080474

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000397.4(CYBB):c.654C>A(p.Gly218Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,206,526 control chromosomes in the GnomAD database, including 1 homozygotes. There are 156 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 0.0028 ( 1 hom., 71 hem., cov: 22)

Exomes 𝑓: 0.00032 ( 0 hom. 85 hem. )

Consequence

CYBB
NM_000397.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.99

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant X-37796121-C-A is Benign according to our data. Variant chrX-37796121-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00282 (315/111813) while in subpopulation AFR AF = 0.00964 (297/30818). AF 95% confidence interval is 0.00874. There are 1 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 71 XL,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4 link	c.654C>A	p.Gly218Gly	synonymous_variant	Exon 6 of 13	ENST00000378588.5	NP_000388.2	P04839A0A0S2Z3S6
CYBB	XM_047441855.1 link	c.348C>A	p.Gly116Gly	synonymous_variant	Exon 5 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5 link	c.654C>A	p.Gly218Gly	synonymous_variant	Exon 6 of 13	1	NM_000397.4	ENSP00000367851.4		P04839
ENSG00000250349	ENST00000465127.1 link	c.171+370121C>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

316

AN:

111757

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00969

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00199

GnomAD2 exomes

AF:

0.000826

AC:

151

AN:

182763

AF XY:

0.000533

show subpopulations

Gnomad AFR exome

AF:

0.0103

Gnomad AMR exome

AF:

0.000585

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000315

AC:

345

AN:

1094713

Hom.:

Cov.:

AF XY:

0.000236

AC XY:

AN XY:

360521

show subpopulations

African (AFR)

AF:

0.0116

AC:

304

AN:

26291

American (AMR)

AF:

0.000513

AC:

AN:

35117

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19345

East Asian (EAS)

AF:

0.00

AC:

AN:

30189

South Asian (SAS)

AF:

0.00

AC:

AN:

54073

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839122

Other (OTH)

AF:

0.000457

AC:

AN:

45951

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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

100

<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:

0.00282

AC:

315

AN:

111813

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

AN XY:

34063

show subpopulations

African (AFR)

AF:

0.00964

AC:

297

AN:

30818

American (AMR)

AF:

0.00133

AC:

AN:

10547

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3525

South Asian (SAS)

AF:

0.000369

AC:

AN:

2710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53090

Other (OTH)

AF:

0.00197

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00145

Hom.:

Bravo

AF:

0.00348

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Granulomatous disease, chronic, X-linked

Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 18, 2011

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

not specified

Benign:1

May 24, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CYBB-related disorder

Benign:1

May 01, 2019

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

3.6

(source)

DANN

Benign

0.70

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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