16-88648099-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000101.4(CYBA):​c.74G>T​(p.Gly25Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G25D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 6.70

Publications

7 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYBANM_000101.4 linkc.74G>T p.Gly25Val missense_variant Exon 2 of 6 ENST00000261623.8 NP_000092.2 P13498B4DT46
CYBAXM_011522905.4 linkc.74G>T p.Gly25Val missense_variant Exon 2 of 6 XP_011521207.1 H3BNP7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYBAENST00000261623.8 linkc.74G>T p.Gly25Val missense_variant Exon 2 of 6 1 NM_000101.4 ENSP00000261623.3 P13498

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152218
Hom.:
0
Cov.:
33
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:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459916
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726198
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44572
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26062
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39654
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85926
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52544
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111604
Other (OTH)
AF:
0.00
AC:
0
AN:
60318
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 15, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CYBA c.74G>T (p.Gly25Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.74G>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Chronic Granulomatous Disease in whom no protein could be detected in the patient's neutrophils (Rae_2000 cited in Roos_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10910929, 34547651). ClinVar contains an entry for this variant (Variation ID: 68213). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Other:1
-
UniProtKB/Swiss-Prot
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;D;.;D
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.7
M;.;.;.
PhyloP100
6.7
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-6.4
D;D;D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
1.0
D;.;.;.
Vest4
0.98
MutPred
0.98
Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP
0.96
MPC
0.78
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.86
gMVP
0.97
Mutation Taster
=1/99
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
Splicevardb
2.0
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs179363891; hg19: chr16-88714507; API