rs200590340

Variant names:

• chr16-88647096-C-T
• rs200590340
• NM_000101.4:c.203+5G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_Strong BS1_Supporting BS2

The NM_000101.4(CYBA):​c.203+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000874 in 1,609,676 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (2 hom.)
• Consequence: CYBA NM_000101.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.50

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 Likely_benign. Variant got -1 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000236 (36/152338) while in subpopulation NFE AF= 0.00047 (32/68026). AF 95% confidence interval is 0.000342. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBA	NM_000101.4	c.203+5G>A		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4	c.203+5G>A		splice_region_variant, intron_variant	Intron 3 of 5		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8	c.203+5G>A		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_000101.4	ENSP00000261623.3

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000242 AC: 59 AN: 244146 Hom.: 0 AF XY: 0.000233 AC XY: 31 AN XY: 132814

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000515

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000941 AC: 1371 AN: 1457338 Hom.: 2 Cov.: 33 AF XY: 0.000905 AC XY: 656 AN XY: 725072

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74492

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000388 Hom.: 0

Bravo AF: 0.000253

EpiCase AF: 0.000327

EpiControl AF: 0.000535

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYBA c.203+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 244146 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYBA causing Chronic Granulomatous Disease (0.00024 vs 0.00061), allowing no conclusion about variant significance. c.203+5G>A has been reported in the literature in one individual affected with Chronic Granulomatous Disease (Sacco_2019). The report does not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31813112). ClinVar contains an entry for this variant (Variation ID: 534660). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Chronic granulomatous disease Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 of the CYBA gene. It does not directly change the encoded amino acid sequence of the CYBA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200590340, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CYBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 534660). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs200590340; hg19: chr16-88713504;