16-88643367-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000101.4(CYBA):​c.574G>A​(p.Asp192Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000459 in 1,526,540 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D192Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.18

Publications

1 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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYBANM_000101.4 linkc.574G>A p.Asp192Asn missense_variant Exon 6 of 6 ENST00000261623.8 NP_000092.2 P13498B4DT46
CYBAXM_011522905.4 linkc.*1799G>A 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>A p.Asp192Asn missense_variant Exon 6 of 6 1 NM_000101.4 ENSP00000261623.3 P13498

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152064
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000165
AC:
2
AN:
121396
AF XY:
0.0000298
show subpopulations
Gnomad AFR exome
AF:
0.000269
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000990
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000437
AC:
6
AN:
1374476
Hom.:
0
Cov.:
32
AF XY:
0.00000443
AC XY:
3
AN XY:
677672
show subpopulations
African (AFR)
AF:
0.0000346
AC:
1
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:
0.0000293
AC:
1
AN:
34098
South Asian (SAS)
AF:
0.00
AC:
0
AN:
77468
European-Finnish (FIN)
AF:
0.0000236
AC:
1
AN:
42420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5098
European-Non Finnish (NFE)
AF:
0.00000280
AC:
3
AN:
1071338
Other (OTH)
AF:
0.00
AC:
0
AN:
56984
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.533
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152064
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74268
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41414
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5150
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67988
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000119
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 16, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.574G>A (p.D192N) alteration is located in exon 6 (coding exon 6) of the CYBA gene. This alteration results from a G to A substitution at nucleotide position 574, causing the aspartic acid (D) at amino acid position 192 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Uncertain:1
Sep 24, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces aspartic acid with asparagine at codon 192 of the CYBA protein (p.Asp192Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CYBA-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.017
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D
Eigen
Benign
0.047
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.83
T
M_CAP
Pathogenic
0.47
D
MetaRNN
Uncertain
0.62
D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.2
M
PhyloP100
2.2
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.2
N
REVEL
Uncertain
0.40
Sift
Uncertain
0.016
D
Sift4G
Uncertain
0.036
D
Polyphen
1.0
D
Vest4
0.39
MutPred
0.57
Loss of phosphorylation at T191 (P = 0.1288);
MVP
0.88
MPC
0.69
ClinPred
0.20
T
GERP RS
4.3
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.18
gMVP
0.44
Mutation Taster
=88/12
polymorphism

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