rs4827298

Variant names:

• chrX-37792410-T-C
• rs4827298
• NM_000397.4:c.337+351T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000397.4(CYBB):​c.337+351T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 109,873 control chromosomes in the GnomAD database, including 10,079 homozygotes. There are 12,869 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (10079 hom., 12869 hem., cov: 22)
• Consequence: CYBB NM_000397.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

  Inheritance: XL, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000397.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	NM_000397.4	MANE Select	c.337+351T>C		intron	N/A	NP_000388.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	ENST00000378588.5	TSL:1 MANE Select	c.337+351T>C		intron	N/A	ENSP00000367851.4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.171+366410T>C		intron	N/A	ENSP00000417050.1
	CYBB	ENST00000696171.1		c.241+351T>C		intron	N/A	ENSP00000512462.1

Frequencies

GnomAD3 genomes AF: 0.418 AC: 45885 AN: 109834 Hom.: 10070 Cov.: 22

Gnomad AFR AF: 0.863

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.0688

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.366

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.418 AC: 45943 AN: 109873 Hom.: 10079 Cov.: 22 AF XY: 0.398 AC XY: 12869 AN XY: 32295

African (AFR) AF: 0.863 AC: 25976 AN: 30086

American (AMR) AF: 0.295 AC: 3031 AN: 10277

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 681 AN: 2628

East Asian (EAS) AF: 0.0681 AC: 239 AN: 3507

South Asian (SAS) AF: 0.268 AC: 709 AN: 2643

European-Finnish (FIN) AF: 0.238 AC: 1367 AN: 5753

Middle Eastern (MID) AF: 0.235 AC: 50 AN: 213

European-Non Finnish (NFE) AF: 0.252 AC: 13222 AN: 52569

Other (OTH) AF: 0.369 AC: 559 AN: 1516

Alfa AF: 0.330 Hom.: 3545

Bravo AF: 0.443

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.31
PhyloP100		-0.24
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

Other links and lift over

dbSNP: rs4827298; hg19: chrX-37651663;