16-88643367-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000101.4(CYBA):​c.574G>T​(p.Asp192Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,476 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. D192N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.18

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYBANM_000101.4 linkc.574G>T p.Asp192Tyr missense_variant Exon 6 of 6 ENST00000261623.8 NP_000092.2 P13498B4DT46
CYBAXM_011522905.4 linkc.*1799G>T 3_prime_UTR_variant Exon 6 of 6 XP_011521207.1 H3BNP7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYBAENST00000261623.8 linkc.574G>T p.Asp192Tyr missense_variant Exon 6 of 6 1 NM_000101.4 ENSP00000261623.3 P13498

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.28e-7
AC:
1
AN:
1374476
Hom.:
0
Cov.:
32
AF XY:
0.00000148
AC XY:
1
AN XY:
677672
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
28868
American (AMR)
AF:
0.00
AC:
0
AN:
33808
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24394
East Asian (EAS)
AF:
0.00
AC:
0
AN:
34098
South Asian (SAS)
AF:
0.0000129
AC:
1
AN:
77468
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
42420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5098
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1071338
Other (OTH)
AF:
0.00
AC:
0
AN:
56984
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Uncertain:1
Feb 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with CYBA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 192 of the CYBA protein (p.Asp192Tyr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.80
D
Eigen
Benign
0.098
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.80
T
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Uncertain
2.6
M
PhyloP100
2.2
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-2.5
D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0090
D
Polyphen
1.0
D
Vest4
0.74
MutPred
0.59
Gain of sheet (P = 0.0221);
MVP
0.89
MPC
0.78
ClinPred
0.90
D
GERP RS
4.3
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.31
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs777676283; hg19: chr16-88709775; API