16-88643576-G-T

Variant names:

• chr16-88643576-G-T
• rs778207143
• NM_000101.4:c.370-5C>A

Variant summary

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

The NM_000101.4(CYBA):​c.370-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,380,242 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYBA NM_000101.4 splice_region, intron
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• 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: G2P, Labcorp Genetics (formerly Invitae)
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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	c.370-5C>A		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4	c.*1590C>A		3_prime_UTR_variant	Exon 6 of 6		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8	c.370-5C>A		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_000101.4	ENSP00000261623.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1380242 Hom.: 0 Cov.: 36 AF XY: 0.00000294 AC XY: 2 AN XY: 681318

African (AFR) AF: 0.00 AC: 0 AN: 31456

American (AMR) AF: 0.00 AC: 0 AN: 35600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25076

East Asian (EAS) AF: 0.00 AC: 0 AN: 35676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077442

Other (OTH) AF: 0.00 AC: 0 AN: 57600

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.85
PhyloP100		0.058
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		Position offset: -5

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

Other links and lift over

dbSNP: rs778207143; hg19: chr16-88709984;