rs2228117

Positions:

• chrX-37803981-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000397.4(CYBB):​c.1002G>A​(p.Lys334=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00969 in 1,209,331 control chromosomes in the GnomAD database, including 698 homozygotes. There are 3,144 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (374 hom., 1570 hem., cov: 22)
  • Exomes 𝑓: 0.0054 (324 hom. 1574 hem.)
• Consequence: CYBB NM_000397.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.153

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-37803981-G-A is Benign according to our data. Variant chrX-37803981-G-A is described in ClinVar as [Benign]. Clinvar id is 464971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37803981-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBB	NM_000397.4	c.1002G>A	p.Lys334=	synonymous_variant	9/13	ENST00000378588.5
CYBB	XM_047441855.1	c.696G>A	p.Lys232=	synonymous_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBB	ENST00000378588.5	c.1002G>A	p.Lys334=	synonymous_variant	9/13	1	NM_000397.4	P1
CYBB	ENST00000696171.1	c.906G>A	p.Lys302=	synonymous_variant	8/12
CYBB	ENST00000492288.1	n.427G>A		non_coding_transcript_exon_variant	4/4	3
CYBB	ENST00000696170.1	c.*511G>A		3_prime_UTR_variant, NMD_transcript_variant	8/12

Frequencies

GnomAD3 genomes AF: 0.0518 AC: 5771 AN: 111434 Hom.: 373 Cov.: 22 AF XY: 0.0465 AC XY: 1564 AN XY: 33668

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000546

Gnomad OTH AF: 0.0347

GnomAD3 exomes AF: 0.0153 AC: 2795 AN: 183062 Hom.: 174 AF XY: 0.0102 AC XY: 691 AN XY: 67652

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000429

Gnomad OTH exome AF: 0.00797

GnomAD4 exome AF: 0.00542 AC: 5945 AN: 1097846 Hom.: 324 Cov.: 31 AF XY: 0.00433 AC XY: 1574 AN XY: 363404

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000425

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0518 AC: 5779 AN: 111485 Hom.: 374 Cov.: 22 AF XY: 0.0465 AC XY: 1570 AN XY: 33729

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.0296

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00113

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000546

Gnomad4 OTH AF: 0.0343

Alfa AF: 0.0224 Hom.: 221

Bravo AF: 0.0601

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Granulomatous disease, chronic, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Chronic granulomatous disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.73

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

Other links and lift over

dbSNP: rs2228117; hg19: chrX-37663234;