rs4782393

chr16-88647093-A-Gchr16-88647093-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000101.4(CYBA):c.203+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,606,018 control chromosomes in the GnomAD database, including 201,103 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15338 hom., cov: 33)
  • Exomes 𝑓: 0.50 (185765 hom.)
• Consequence: CYBA NM_000101.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001193
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -3.29

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-88647093-A-G is Benign according to our data. Variant chr16-88647093-A-G is described in ClinVar as [Benign]. Clinvar id is 196207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88647093-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBA	NM_000101.4	c.203+8T>C		splice_region_variant, intron_variant		ENST00000261623.8
CYBA	XM_011522905.4	c.203+8T>C		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBA	ENST00000261623.8	c.203+8T>C		splice_region_variant, intron_variant		1	NM_000101.4	P1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66881 AN: 151974 Hom.: 15322 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.471 AC: 113926 AN: 241700 Hom.: 27931 AF XY: 0.471 AC XY: 61919 AN XY: 131448

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.545

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.248

Gnomad SAS exome AF: 0.459

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.510

Gnomad OTH exome AF: 0.464

GnomAD4 exome AF: 0.500 AC: 727537 AN: 1453926 Hom.: 185765 Cov.: 33 AF XY: 0.499 AC XY: 361289 AN XY: 723468

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.536

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.211

Gnomad4 SAS exome AF: 0.461

Gnomad4 FIN exome AF: 0.530

Gnomad4 NFE exome AF: 0.521

Gnomad4 OTH exome AF: 0.477

GnomAD4 genome AF: 0.440 AC: 66918 AN: 152092 Hom.: 15338 Cov.: 33 AF XY: 0.438 AC XY: 32557 AN XY: 74358

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.448

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.438

Alfa AF: 0.471 Hom.: 3212

Bravo AF: 0.432

Asia WGS AF: 0.339 AC: 1180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 74% of patients studied by a panel of primary immunodeficiencies. Number of patients: 70. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Chronic granulomatous disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.59
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs4782393; hg19: chr16-88713501; COSMIC: COSV55369250; COSMIC: COSV55369250;