16-88643538-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000101.4(CYBA):c.403G>A(p.Glu135Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000575 in 1,535,006 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E135Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.63

Publications

6 publications found

Variant links:

Genes affected

CYBA (HGNC:2577): (cytochrome b-245 alpha chain) Cytochrome b is comprised of a light chain (alpha) and a heavy chain (beta). This gene encodes the light, alpha subunit which has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Mutations in this gene are associated with autosomal recessive chronic granulomatous disease (CGD), that is characterized by the failure of activated phagocytes to generate superoxide, which is important for the microbicidal activity of these cells. [provided by RefSeq, Jul 2008]

CYBA Gene-Disease associations (from GenCC):

granulomatous disease, chronic, autosomal recessive, cytochrome b-negative
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
chronic granulomatous disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYBA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0098926425).

BP6

Variant 16-88643538-C-T is Benign according to our data. Variant chr16-88643538-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289491.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00281 (428/152194) while in subpopulation AFR AF = 0.00946 (393/41530). AF 95% confidence interval is 0.00869. There are 0 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBA	NM_000101.4 link	c.403G>A	p.Glu135Lys	missense_variant	Exon 6 of 6	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4 link	c.*1628G>A		3_prime_UTR_variant	Exon 6 of 6		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8 link	c.403G>A	p.Glu135Lys	missense_variant	Exon 6 of 6	1	NM_000101.4	ENSP00000261623.3

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00949

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.000706

AC:

AN:

131780

AF XY:

0.000677

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.000613

Gnomad ASJ exome

AF:

0.000371

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000122

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000328

AC:

454

AN:

1382812

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

202

AN XY:

682780

show subpopulations

African (AFR)

AF:

0.00970

AC:

306

AN:

31554

American (AMR)

AF:

0.000588

AC:

AN:

35734

Ashkenazi Jewish (ASJ)

AF:

0.000399

AC:

AN:

25092

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35836

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34864

Middle Eastern (MID)

AF:

0.00172

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.0000510

AC:

AN:

1078782

Other (OTH)

AF:

0.000902

AC:

AN:

57678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

119

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:

0.00281

AC:

428

AN:

152194

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00946

AC:

393

AN:

41530

American (AMR)

AF:

0.000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67972

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00314

ESP6500AA

AF:

0.00309

AC:

ESP6500EA

AF:

0.000321

AC:

ExAC

AF:

0.000447

AC:

Asia WGS

AF:

0.00203

AC:

AN:

3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYBA: BS1 -

Jun 28, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The E135K variant has been published previously as as a benign variant (Rae et al., 2000). The NHLBI Exome Sequencing Project reports the variant was observed in 9/2910 (0.31%) alleles from individuals of African-American background, and the 1000 Genomes Project Consortium reports E135K was observed in 18/1322 (1.36%) alleles from individuals of African background, indicating it may be a rare variant in these populations. However, the variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Benign:1

Jul 19, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CYBA-related disorder

Benign:1

Mar 25, 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). -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.86

MetaRNN

Benign

0.0099

MetaSVM

Uncertain

0.076

MutationAssessor

Uncertain

2.6

PhyloP100

3.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.66

Sift

Benign

0.28

Sift4G

Benign

0.29

Polyphen

1.0

Vest4

0.51

MVP

0.90

MPC

0.74

ClinPred

0.021

GERP RS

4.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.23

gMVP

0.59

Mutation Taster

=81/19

polymorphism

(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