rs4673

Positions:

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

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:12O: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]

CYBA links:

Genome browser will be placed here

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	Protein	UniProt
CYBA	NM_000101.4 linkuse as main transcript	c.214T>C	p.Tyr72His	missense_variant	4/6	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4 linkuse as main transcript	c.214T>C	p.Tyr72His	missense_variant	4/6		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8 linkuse as main transcript	c.214T>C	p.Tyr72His	missense_variant	4/6	1	NM_000101.4	ENSP00000261623	P1

Frequencies

GnomAD3 genomes

AF:

0.653

AC:

99158

AN:

151878

Hom.:

32915

Cov.:

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.:

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.:

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:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2021	Variant 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 provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This 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. -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This 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 provided	phenotyping only	GenomeConnect, 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 provided

research

Institute of Clinical Molecular Biology, Kiel University

Nov 06, 2018

- -

Chronic granulomatous disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 18, 2019

- -

CYBA POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0000012

MutationTaster

Benign

0.046

P;P;P

PROVEAN

Uncertain

-4.0

ClinPred

0.063

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over