16-88643367-C-G

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>C​(p.Asp192His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,526,540 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: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter 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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYBANM_000101.4 linkc.574G>C p.Asp192His missense_variant Exon 6 of 6 ENST00000261623.8 NP_000092.2 P13498B4DT46
CYBAXM_011522905.4 linkc.*1799G>C 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>C p.Asp192His 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:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00000824
AC:
1
AN:
121396
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000442
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:
7.28e-7
AC:
1
AN:
1374476
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
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:
0.0000296
AC:
1
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:
0.00
AC:
0
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: 0.325
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
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:
0.00
AC:
0
AN:
41414
American (AMR)
AF:
0.0000654
AC:
1
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: 0.575
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:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Chronic granulomatous disease Uncertain:1
Aug 29, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Uncertain:1
Nov 05, 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, which is acidic and polar, with histidine, which is basic and polar, at codon 192 of the CYBA protein (p.Asp192His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CYBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 948436). 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
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.61
D
Eigen
Benign
0.094
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.79
T
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.85
D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Uncertain
2.6
M
PhyloP100
2.2
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.62
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.017
D
Polyphen
1.0
D
Vest4
0.59
MutPred
0.58
Gain of glycosylation at T191 (P = 0.1078);
MVP
0.89
MPC
0.77
ClinPred
0.82
D
GERP RS
4.3
Varity_R
0.21
gMVP
0.51

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