Genetic Variant NM_000101.4:c.576C>G (chr16-88643365-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000101.4(CYBA):c.576C>G(p.Asp192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,374,932 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D192N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.28

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBA	NM_000101.4 link	c.576C>G	p.Asp192Glu	missense_variant	Exon 6 of 6	ENST00000261623.8	NP_000092.2	P13498B4DT46
CYBA	XM_011522905.4 link	c.*1801C>G		3_prime_UTR_variant	Exon 6 of 6		XP_011521207.1	H3BNP7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8 link	c.576C>G	p.Asp192Glu	missense_variant	Exon 6 of 6	1	NM_000101.4	ENSP00000261623.3		P13498

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000291

AC:

AN:

1374932

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

677846

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28878

American (AMR)

AF:

0.00

AC:

AN:

33772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24422

East Asian (EAS)

AF:

0.00

AC:

AN:

34146

South Asian (SAS)

AF:

0.00

AC:

AN:

77468

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5170

European-Non Finnish (NFE)

AF:

0.00000373

AC:

AN:

1071662

Other (OTH)

AF:

0.00

AC:

AN:

57070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

0.00062

BayesDel_noAF

Benign

-0.24

CADD

Benign

1.2

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.48

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.2

PhyloP100

-1.3

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.46

Sift

Benign

0.21

Sift4G

Benign

0.40

Polyphen

1.0

Vest4

0.32

MutPred

0.57

Loss of phosphorylation at T191 (P = 0.2117);

MVP

0.53

MPC

0.67

ClinPred

0.76

GERP RS

-8.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.055

gMVP

0.36

Mutation Taster

=96/4

polymorphism

(source)

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

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NM_000101.4:c.576C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over