rs151344452

chrX-37809656-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain 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 GnomAd at 41 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.1551T>A	p.Asp517Glu	missense_variant	12/13	ENST00000378588.5
CYBB	XM_047441855.1	c.1245T>A	p.Asp415Glu	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.1551T>A	p.Asp517Glu	missense_variant	12/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.1455T>A	p.Asp485Glu	missense_variant	11/12
CYBB	ENST00000696170.1	c.*1060T>A		3_prime_UTR_variant, NMD_transcript_variant	11/12

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 155 AN: 111796 Hom.: 1 Cov.: 23 AF XY: 0.00121 AC XY: 41 AN XY: 33988

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.: 0 AF XY: 0.00108 AC XY: 67 AN XY: 62122

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.: 3 Cov.: 30 AF XY: 0.00203 AC XY: 734 AN XY: 361337

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.: 1 Cov.: 23 AF XY: 0.00123 AC XY: 42 AN XY: 34051

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.: 9

Bravo AF: 0.00113

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00242 AC: 7

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.00134 AC: 162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 02, 2016	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2018	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. -

Granulomatous disease, chronic, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

CYBB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2020

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	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Benign	0.23	T
Sift4G	Benign	0.21	T
Polyphen		0.0040	B
Vest4		0.048
MutPred		0.17		Loss of loop (P = 0.0804);
MVP		0.92
MPC		0.57
ClinPred		0.016	T
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

Other links and lift over

dbSNP: rs151344452; hg19: chrX-37668909;