rs35080474

chrX-37796121-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000397.4(CYBB):c.654C>A(p.Gly218=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,206,526 control chromosomes in the GnomAD database, including 1 homozygotes. There are 156 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 0.0028 (1 hom., 71 hem., cov: 22)
  • Exomes 𝑓: 0.00032 (0 hom. 85 hem.)
• Consequence: CYBB NM_000397.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.99

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-37796121-C-A is Benign according to our data. Variant chrX-37796121-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 35975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37796121-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00282 (315/111813) while in subpopulation AFR AF= 0.00964 (297/30818). AF 95% confidence interval is 0.00874. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 72 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.654C>A	p.Gly218=	synonymous_variant	6/13	ENST00000378588.5
CYBB	XM_047441855.1	c.348C>A	p.Gly116=	synonymous_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.654C>A	p.Gly218=	synonymous_variant	6/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.558C>A	p.Gly186=	synonymous_variant	5/12
CYBB	ENST00000696170.1	c.*163C>A		3_prime_UTR_variant, NMD_transcript_variant	5/12
CYBB	ENST00000696172.1	c.338-2834C>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 316 AN: 111757 Hom.: 1 Cov.: 22 AF XY: 0.00212 AC XY: 72 AN XY: 33997

Gnomad AFR AF: 0.00969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000826 AC: 151 AN: 182763 Hom.: 0 AF XY: 0.000533 AC XY: 36 AN XY: 67509

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000315 AC: 345 AN: 1094713 Hom.: 0 Cov.: 31 AF XY: 0.000236 AC XY: 85 AN XY: 360521

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000513

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.000457

GnomAD4 genome AF: 0.00282 AC: 315 AN: 111813 Hom.: 1 Cov.: 22 AF XY: 0.00208 AC XY: 71 AN XY: 34063

Gnomad4 AFR AF: 0.00964

Gnomad4 AMR AF: 0.00133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000369

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.00154 Hom.: 14

Bravo AF: 0.00348

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Granulomatous disease, chronic, X-linked Benign:2

Likely benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 24, 2017

- -

CYBB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

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
BayesDel_noAF	Benign	-0.49
Cadd	Benign	3.6
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs35080474; hg19: chrX-37655374;