16-88643400-C-G

Position:

• chr16-88643400-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000101.4(CYBA):​c.541G>C​(p.Gly181Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CYBA NM_000101.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41538942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYBA	NM_000101.4	c.541G>C	p.Gly181Arg	missense_variant	6/6	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4	c.*1766G>C		3_prime_UTR_variant	6/6		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8	c.541G>C	p.Gly181Arg	missense_variant	6/6	1	NM_000101.4	ENSP00000261623.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74278

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.541G>C (p.G181R) alteration is located in exon 6 (coding exon 6) of the CYBA gene. This alteration results from a G to C substitution at nucleotide position 541, causing the glycine (G) at amino acid position 181 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces glycine with arginine at codon 181 of the CYBA protein (p.Gly181Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with CYBA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.87	P
Vest4		0.14
MutPred		0.69		Gain of solvent accessibility (P = 0.0037);
MVP		0.82
MPC		0.75
ClinPred		0.74	D
GERP RS		3.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.16
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs1413781990; hg19: chr16-88709808;