NM_000101.4:c.269G>C

Variant names:

• chr16-88646773-C-G
• rs104894513
• NM_000101.4:c.269G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000101.4(CYBA):​c.269G>C​(p.Arg90Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYBA NM_000101.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.49
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), G2P
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a helix (size 14) in uniprot entity CY24A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000101.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88646774-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 16-88646773-C-G is Pathogenic according to our data. Variant chr16-88646773-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3768887.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000101.4. 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
	CYBA	NM_000101.4	MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 4 of 6	NP_000092.2	P13498

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBA	ENST00000261623.8	TSL:1 MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 4 of 6	ENSP00000261623.3	P13498
	CYBA	ENST00000569359.5	TSL:1	c.269G>C	p.Arg90Pro	missense	Exon 4 of 5	ENSP00000456079.1	H3BR52
	CYBA	ENST00000967613.1		c.269G>C	p.Arg90Pro	missense	Exon 4 of 7	ENSP00000637672.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Chronic granulomatous disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.97		Loss of methylation at R90 (P = 0.0202)
MVP		0.96
MPC		0.85
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.018	Neutral
Varity_R		0.93
gMVP		1.0
Mutation Taster		=7/93	disease causing

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: rs104894513; hg19: chr16-88713181;