NM_000397.4:c.676C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong

The NM_000397.4(CYBB):c.676C>T(p.Arg226*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,757 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000616695: Published functional studies demonstrated lack of protein expression in neutrophil cells of affected individuals with the p.(R226X) variant (Sun et al., 2012)" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CYBB
NM_000397.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.1092

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.11

Publications

32 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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)

CYBB links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000616695: Published functional studies demonstrated lack of protein expression in neutrophil cells of affected individuals with the p.(R226X) variant (Sun et al., 2012);; SCV000883704: Functional characterization indicates that the variant leads to the loss of NAPDH-oxidase activity (Curnette 1992, von Goessel 2006, Kannengiesser 2008), resulting in functionally defective neurophils (Kannengiesser 2008).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-37798956-C-T is Pathogenic according to our data. Variant chrX-37798956-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	NM_000397.4	MANE Select	c.676C>T	p.Arg226*	stop_gained splice_region	Exon 7 of 13	NP_000388.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYBB	ENST00000378588.5	TSL:1 MANE Select	c.676C>T	p.Arg226*	stop_gained splice_region	Exon 7 of 13	ENSP00000367851.4	P04839
ENSG00000250349	ENST00000465127.1	TSL:5	c.171+372956C>T		intron	N/A	ENSP00000417050.1	B4E171
CYBB	ENST00000968558.1		c.676C>T	p.Arg226*	stop_gained splice_region	Exon 7 of 14	ENSP00000638617.1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111757

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000578

AC:

AN:

173035

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000801

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1091611

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358473

African (AFR)

AF:

0.00

AC:

AN:

26176

American (AMR)

AF:

0.00

AC:

AN:

34848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19240

East Asian (EAS)

AF:

0.00

AC:

AN:

29941

South Asian (SAS)

AF:

0.00

AC:

AN:

53574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

837655

Other (OTH)

AF:

0.00

AC:

AN:

45773

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111757

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34033

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30759

American (AMR)

AF:

0.00

AC:

AN:

10534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53084

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Granulomatous disease, chronic, X-linked (5)

not provided (4)

Chronic granulomatous disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.46

PhyloP100

1.1

Vest4

0.96

GERP RS

3.1

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over