Genetic Variant CYBA:c.288-126G>A (chr16-88646323-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000101.4(CYBA):c.288-126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 661,906 control chromosomes in the GnomAD database, including 173 homozygotes. 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 0.00027 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0045 ( 173 hom. )

Consequence

CYBA
NM_000101.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.50

Publications

8 publications found

Variant links:

Genes affected

CYBA (HGNC:2577): (cytochrome b-245 alpha chain) Cytochrome b is comprised of a light chain (alpha) and a heavy chain (beta). This gene encodes the light, alpha subunit which has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Mutations in this gene are associated with autosomal recessive chronic granulomatous disease (CGD), that is characterized by the failure of activated phagocytes to generate superoxide, which is important for the microbicidal activity of these cells. [provided by RefSeq, Jul 2008]

CYBA Gene-Disease associations (from GenCC):

granulomatous disease, chronic, autosomal recessive, cytochrome b-negative
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
chronic granulomatous disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYBA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000271 (27/99722) while in subpopulation AMR AF = 0.000504 (5/9928). AF 95% confidence interval is 0.000318. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 173 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBA	NM_000101.4 link	c.288-126G>A		intron_variant	Intron 4 of 5	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4 link	c.288-126G>A		intron_variant	Intron 4 of 5		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8 link	c.288-126G>A		intron_variant	Intron 4 of 5	1	NM_000101.4	ENSP00000261623.3

Frequencies

GnomAD3 genomes

AF:

0.000271

AC:

AN:

99604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000504

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000149

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000107

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00446

AC:

2507

AN:

562184

Hom.:

173

Cov.:

AF XY:

0.00416

AC XY:

1225

AN XY:

294384

show subpopulations

African (AFR)

AF:

0.00165

AC:

AN:

17014

American (AMR)

AF:

0.00293

AC:

AN:

25596

Ashkenazi Jewish (ASJ)

AF:

0.00313

AC:

AN:

16620

East Asian (EAS)

AF:

0.000100

AC:

AN:

30006

South Asian (SAS)

AF:

0.00399

AC:

214

AN:

53612

European-Finnish (FIN)

AF:

0.000939

AC:

AN:

27700

Middle Eastern (MID)

AF:

0.00442

AC:

AN:

3620

European-Non Finnish (NFE)

AF:

0.00555

AC:

1988

AN:

358224

Other (OTH)

AF:

0.00352

AC:

105

AN:

29792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

191

287

382

478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000271

AC:

AN:

99722

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

49356

show subpopulations

African (AFR)

AF:

0.000500

AC:

AN:

33998

American (AMR)

AF:

0.000504

AC:

AN:

9928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2164

East Asian (EAS)

AF:

0.00

AC:

AN:

4308

South Asian (SAS)

AF:

0.00

AC:

AN:

3272

European-Finnish (FIN)

AF:

0.000149

AC:

AN:

6692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

198

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

37390

Other (OTH)

AF:

0.00

AC:

AN:

1302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.182

Hom.:

375

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.8

(source)

DANN

Benign

0.54

PhyloP100

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over