rs13306300

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2

The NM_000397.4(CYBB):c.1414G>A(p.Gly472Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000495 in 1,209,121 control chromosomes in the GnomAD database, including 2 homozygotes. There are 199 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G472G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 15 hem., cov: 22)

Exomes 𝑓: 0.00051 ( 2 hom. 184 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.94

Variant links:

Genes affected

CYBB (HGNC:2578): (cytochrome b-245 beta chain) Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]

CYBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 287) in uniprot entity CY24B_HUMAN there are 53 pathogenic changes around while only 20 benign (73%) in NM_000397.4

BP4

Computational evidence support a benign effect (MetaRNN=0.01174444).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000304 (34/111666) while in subpopulation EAS AF= 0.00935 (33/3530). AF 95% confidence interval is 0.00684. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4 linkuse as main transcript	c.1414G>A	p.Gly472Ser	missense_variant	11/13	ENST00000378588.5
CYBB	XM_047441855.1 linkuse as main transcript	c.1108G>A	p.Gly370Ser	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CYBB	ENST00000378588.5 linkuse as main transcript	c.1414G>A	p.Gly472Ser	missense_variant	11/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1 linkuse as main transcript	c.1318G>A	p.Gly440Ser	missense_variant	10/12
CYBB	ENST00000696170.1 linkuse as main transcript	c.*923G>A		3_prime_UTR_variant, NMD_transcript_variant	10/12

Frequencies

GnomAD3 genomes

AF:

0.000305

AC:

AN:

111612

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

33812

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00932

Gnomad SAS

AF:

0.000372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000893

AC:

163

AN:

182459

Hom.:

AF XY:

0.000640

AC XY:

AN XY:

67239

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0111

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000737

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.000514

AC:

564

AN:

1097455

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

184

AN XY:

362987

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0171

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000368

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.000304

AC:

AN:

111666

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

33876

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00935

Gnomad4 SAS

AF:

0.000373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000743

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000807

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CYBB-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2023

The CYBB c.1414G>A variant is predicted to result in the amino acid substitution p.Gly472Ser. This variant has been reported in male patients with X-linked chronic granulomatous disease and respiratory phenotypes (Patient 85, Chiu et al. 2021. PubMed ID: 35140711; Table S2, Patient 100, Dai et al. 2021. PubMed ID: 34134972). It has also been reported in a female patient with pneumonia, lymphadenitis, allergic rhinitis, maxillary sinusitis, adenoid hypertrophy, acanthosis nigricans, moderate anemia, EBV infection (Patient 17, Wu et al. 2017. PubMed ID: 28251166). This variant is reported in 1.1% of alleles in individuals of East Asian descent in gnomAD, including 45 hemizygotes in that subpopulation (http://gnomad.broadinstitute.org/variant/X-37665739-G-A), which may be too common to be causative. This variant is also reported as likely benign/benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/732210/). However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 20, 2022

Variant summary: CYBB c.1414G>A (p.Gly472Ser) results in a non-conservative amino acid change located in the Ferric reductase, NAD binding domain (IPR013121) of 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 0.00084 in 204242 control chromosomes (gnomAD), with 48 hemizygotes. The variant occurs predominantly at a frequency of 0.011 within the East Asian subpopulation in the gnomAD database, including 45 hemizygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYBB causing X-Linked Chronic Granulomatous Disease (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Granulomatous disease, chronic, X-linked

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

CYBB: BS1, BS2 -

Granulomatous disease, chronic, X-linked;C1970859:X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Chronic granulomatous disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Benign

0.83

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.81

MetaRNN

Benign

0.012

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.42

REVEL

Benign

0.21

Sift

Benign

0.090

Sift4G

Benign

0.14

Polyphen

0.097

Vest4

0.056

MVP

0.86

MPC

0.65

ClinPred

0.020

GERP RS

3.8

Varity_R

0.22

gMVP

0.59

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