rs12848910

Variant names:

• chrX-37806992-A-G
• rs12848910
• NM_000397.4:c.1461+459A>G

Variant summary

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

The NM_000397.4(CYBB):​c.1461+459A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.059 in 110,697 control chromosomes in the GnomAD database, including 202 homozygotes. There are 1,893 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 0.059 (202 hom., 1893 hem., cov: 22)
• Consequence: CYBB NM_000397.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.089 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.1461+459A>G		intron_variant	Intron 11 of 12	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.1155+459A>G		intron_variant	Intron 10 of 11		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.1461+459A>G		intron_variant	Intron 11 of 12	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+380992A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
CYBB	ENST00000696171.1	c.1365+459A>G		intron_variant	Intron 10 of 11			ENSP00000512462.1
CYBB	ENST00000696170.1	n.*970+459A>G		intron_variant	Intron 10 of 11			ENSP00000512461.1

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 6538 AN: 110650 Hom.: 203 Cov.: 22

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0982

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0911

Gnomad OTH AF: 0.0531

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

GnomAD4 genome AF: 0.0590 AC: 6534 AN: 110697 Hom.: 202 Cov.: 22 AF XY: 0.0575 AC XY: 1893 AN XY: 32945

African (AFR) AF: 0.0111 AC: 339 AN: 30489

American (AMR) AF: 0.0459 AC: 476 AN: 10364

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 149 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.0118 AC: 31 AN: 2622

European-Finnish (FIN) AF: 0.0982 AC: 570 AN: 5807

Middle Eastern (MID) AF: 0.0370 AC: 8 AN: 216

European-Non Finnish (NFE) AF: 0.0911 AC: 4814 AN: 52841

Other (OTH) AF: 0.0525 AC: 79 AN: 1505

Alfa AF: 0.0727 Hom.: 2401

Bravo AF: 0.0523

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.1
DANN	Benign	0.78
PhyloP100		1.2
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: rs12848910; hg19: chrX-37666245;