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GeneBe

rs4673

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000101.4(CYBA):c.214T>C(p.Tyr72His) variant causes a missense change. The variant allele was found at a frequency of 0.672 in 1,612,206 control chromosomes in the GnomAD database, including 367,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32939 hom., cov: 32)
Exomes 𝑓: 0.67 ( 334674 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

5
5

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:11O:1

Conservation

PhyloP100: 4.22
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.2247359E-6).
BP6
Variant 16-88646828-A-G is Benign according to our data. Variant chr16-88646828-A-G is described in ClinVar as [Benign]. Clinvar id is 2263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88646828-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYBANM_000101.4 linkuse as main transcriptc.214T>C p.Tyr72His missense_variant 4/6 ENST00000261623.8
CYBAXM_011522905.4 linkuse as main transcriptc.214T>C p.Tyr72His missense_variant 4/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYBAENST00000261623.8 linkuse as main transcriptc.214T>C p.Tyr72His missense_variant 4/61 NM_000101.4 P1

Frequencies

GnomAD3 genomes
AF:
0.653
AC:
99158
AN:
151878
Hom.:
32915
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.544
Gnomad AMI
AF:
0.690
Gnomad AMR
AF:
0.722
Gnomad ASJ
AF:
0.579
Gnomad EAS
AF:
0.910
Gnomad SAS
AF:
0.643
Gnomad FIN
AF:
0.824
Gnomad MID
AF:
0.551
Gnomad NFE
AF:
0.663
Gnomad OTH
AF:
0.636
GnomAD3 exomes
AF:
0.698
AC:
174863
AN:
250626
Hom.:
62429
AF XY:
0.690
AC XY:
93689
AN XY:
135686
show subpopulations
Gnomad AFR exome
AF:
0.551
Gnomad AMR exome
AF:
0.771
Gnomad ASJ exome
AF:
0.568
Gnomad EAS exome
AF:
0.914
Gnomad SAS exome
AF:
0.634
Gnomad FIN exome
AF:
0.822
Gnomad NFE exome
AF:
0.668
Gnomad OTH exome
AF:
0.666
GnomAD4 exome
AF:
0.674
AC:
983701
AN:
1460210
Hom.:
334674
Cov.:
44
AF XY:
0.672
AC XY:
488360
AN XY:
726538
show subpopulations
Gnomad4 AFR exome
AF:
0.541
Gnomad4 AMR exome
AF:
0.760
Gnomad4 ASJ exome
AF:
0.580
Gnomad4 EAS exome
AF:
0.906
Gnomad4 SAS exome
AF:
0.634
Gnomad4 FIN exome
AF:
0.813
Gnomad4 NFE exome
AF:
0.665
Gnomad4 OTH exome
AF:
0.666
GnomAD4 genome
AF:
0.653
AC:
99225
AN:
151996
Hom.:
32939
Cov.:
32
AF XY:
0.661
AC XY:
49133
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.543
Gnomad4 AMR
AF:
0.723
Gnomad4 ASJ
AF:
0.579
Gnomad4 EAS
AF:
0.910
Gnomad4 SAS
AF:
0.643
Gnomad4 FIN
AF:
0.824
Gnomad4 NFE
AF:
0.663
Gnomad4 OTH
AF:
0.639
Alfa
AF:
0.657
Hom.:
79978
Bravo
AF:
0.643
TwinsUK
AF:
0.645
AC:
2393
ALSPAC
AF:
0.668
AC:
2573
ESP6500AA
AF:
0.553
AC:
2432
ESP6500EA
AF:
0.657
AC:
5646
ExAC
AF:
0.690
AC:
83753
Asia WGS
AF:
0.764
AC:
2654
AN:
3478
EpiCase
AF:
0.639
EpiControl
AF:
0.643

ClinVar

Significance: Benign
Submissions summary: Pathogenic:1Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This variant is classified as Benign based on local population frequency. This variant was detected in 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 88. Only high quality variants are reported. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 16, 2021Variant summary: CYBA c.214T>C (p.Tyr72His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.7 in 250626 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 1139 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYBA causing Chronic Granulomatous Disease phenotype (0.00061), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.214T>C in individuals affected with Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the clinical significance of this variant after 2014: four have classified the variant as benign and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Benign:3
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJun 10, 2021- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
not provided Benign:1Other:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 30709874, 17383305, 21884584, 18799874, 19689263, 11023926, 15078863, 23821607, 22396743, 23409188, 25095657, 23040216, 9445163, 24339896, 24392120, 29132304, 29454792) -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Very early onset inflammatory bowel disease Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchInstitute of Clinical Molecular Biology, Kiel UniversityNov 06, 2018- -
CYBA POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMJul 01, 2009- -
Chronic granulomatous disease Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Nov 18, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Uncertain
-0.080
Cadd
Benign
21
Dann
Uncertain
0.99
Eigen
Uncertain
0.30
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.96
D
MetaRNN
Benign
0.0000012
T
MutationTaster
Benign
0.046
P;P;P
PROVEAN
Uncertain
-4.0
D
ClinPred
0.063
T
GERP RS
3.5
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4673; hg19: chr16-88713236; COSMIC: COSV55368224; COSMIC: COSV55368224; API