chrX-37803981-G-A

Variant names:

• chrX-37803981-G-A
• rs2228117
• NM_000397.4:c.1002G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000397.4(CYBB):​c.1002G>A​(p.Lys334Lys) 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:4
• 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]

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.1002G>A	p.Lys334Lys	synonymous_variant	Exon 9 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.696G>A	p.Lys232Lys	synonymous_variant	Exon 8 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.1002G>A	p.Lys334Lys	synonymous_variant	Exon 9 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+377981G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0518 AC: 5771 AN: 111434 Hom.: 373 Cov.: 22

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

GnomAD2 exomes AF: 0.0153 AC: 2795 AN: 183062 AF XY: 0.0102

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 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 AC: 4638 AN: 26371

Gnomad4 AMR exome AF: 0.0122 AC: 430 AN: 35132

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19374

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30196

Gnomad4 SAS exome AF: 0.000425 AC: 23 AN: 54146

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40529

Gnomad4 NFE exome AF: 0.000244 AC: 205 AN: 841889

Gnomad4 Remaining exome AF: 0.0137 AC: 633 AN: 46078

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 AC: 0.17609 AN: 0.17609

Gnomad4 AMR AF: 0.0296 AC: 0.0295791 AN: 0.0295791

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00113 AC: 0.00113293 AN: 0.00113293

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000546 AC: 0.000546253 AN: 0.000546253

Gnomad4 OTH AF: 0.0343 AC: 0.0342782 AN: 0.0342782

Alfa AF: 0.0224 Hom.: 221

Bravo AF: 0.0601

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Granulomatous disease, chronic, X-linked Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chronic granulomatous disease Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.73
Mutation Taster		=100/0	polymorphism (auto)

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;