rs151344452

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000397.4(CYBB):c.1551T>A(p.Asp517Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,207,338 control chromosomes in the GnomAD database, including 4 homozygotes. There are 776 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., 42 hem., cov: 23)

Exomes 𝑓: 0.0022 ( 3 hom. 734 hem. )

Consequence

CYBB
NM_000397.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 1.26

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:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 287) in uniprot entity CY24B_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000397.4

BP4

Computational evidence support a benign effect (MetaRNN=0.018161982).

BP6

Variant X-37809656-T-A is Benign according to our data. Variant chrX-37809656-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 68385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37809656-T-A is described in Lovd as [Benign]. Variant chrX-37809656-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00139 (156/111849) while in subpopulation NFE AF= 0.00252 (134/53122). AF 95% confidence interval is 0.00217. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 42 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4 link	c.1551T>A	p.Asp517Glu	missense_variant	Exon 12 of 13	ENST00000378588.5	NP_000388.2	P04839A0A0S2Z3S6
CYBB	XM_047441855.1 link	c.1245T>A	p.Asp415Glu	missense_variant	Exon 11 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5 link	c.1551T>A	p.Asp517Glu	missense_variant	Exon 12 of 13	1	NM_000397.4	ENSP00000367851.4		P04839
ENSG00000250349	ENST00000465127.1 link	c.171+383656T>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

155

AN:

111796

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

33988

show subpopulations

Gnomad AFR

AF:

0.000228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000762

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.000164

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00252

Gnomad OTH

AF:

0.000666

GnomAD3 exomes

AF:

0.00118

AC:

209

AN:

176958

Hom.:

AF XY:

0.00108

AC XY:

AN XY:

62122

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.000446

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00107

Gnomad FIN exome

AF:

0.000193

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.00215

AC:

2360

AN:

1095489

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

734

AN XY:

361337

show subpopulations

Gnomad4 AFR exome

AF:

0.000228

Gnomad4 AMR exome

AF:

0.000400

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00105

Gnomad4 FIN exome

AF:

0.000272

Gnomad4 NFE exome

AF:

0.00263

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00139

AC:

156

AN:

111849

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

34051

show subpopulations

Gnomad4 AFR

AF:

0.000227

Gnomad4 AMR

AF:

0.000761

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00150

Gnomad4 FIN

AF:

0.000164

Gnomad4 NFE

AF:

0.00252

Gnomad4 OTH

AF:

0.000658

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.00113

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00242

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00134

AC:

162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 02, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Dec 04, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYBB c.1551T>A (p.Asp517Glu) results in a conservative amino acid change located in the Ferric reductase, NAD binding domain 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 0.0012 in 193905 control chromosomes, including 75 hemizygous males, predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CYBB causing X-linked Chronic Granulomatous Disease phenotype (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.1551T>A, has been reported in the literature in one individual affected with X-linked Chronic Granulomatous Disease as a benign variant, together with c.90C>A (p.Y30X)(Hill_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Granulomatous disease, chronic, X-linked

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CYBB-related disorder

Benign:1

Sep 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.018

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.72

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.31

Sift

Benign

0.23

Sift4G

Benign

0.21

Polyphen

0.0040

Vest4

0.048

MutPred

0.17

Loss of loop (P = 0.0804);

MVP

0.92

MPC

0.57

ClinPred

0.016

GERP RS

3.3

Varity_R

0.35

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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