rs4673

chr16-88646828-A-Gchr16-88646828-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.214T>C(p.Tyr72His) variant causes a missense change. The variant allele was found at a frequency of 0.672 in 1,612,206 control chromosomes in the GnomAD database, including 367,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32939 hom., cov: 32)
  • Exomes 𝑓: 0.67 (334674 hom.)
• Consequence: CYBA NM_000101.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:11 O:1
• Conservation: PhyloP100: 4.22

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 (MetaRNN=1.2247359E-6).
• BP6: Variant 16-88646828-A-G is Benign according to our data. Variant chr16-88646828-A-G is described in ClinVar as [Benign]. Clinvar id is 2263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88646828-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBA	NM_000101.4	c.214T>C	p.Tyr72His	missense_variant	4/6	ENST00000261623.8
CYBA	XM_011522905.4	c.214T>C	p.Tyr72His	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBA	ENST00000261623.8	c.214T>C	p.Tyr72His	missense_variant	4/6	1	NM_000101.4	P1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99158 AN: 151878 Hom.: 32915 Cov.: 32

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.690

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.636

GnomAD3 exomes AF: 0.698 AC: 174863 AN: 250626 Hom.: 62429 AF XY: 0.690 AC XY: 93689 AN XY: 135686

Gnomad AFR exome AF: 0.551

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.568

Gnomad EAS exome AF: 0.914

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.822

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.674 AC: 983701 AN: 1460210 Hom.: 334674 Cov.: 44 AF XY: 0.672 AC XY: 488360 AN XY: 726538

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.760

Gnomad4 ASJ exome AF: 0.580

Gnomad4 EAS exome AF: 0.906

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.813

Gnomad4 NFE exome AF: 0.665

Gnomad4 OTH exome AF: 0.666

GnomAD4 genome AF: 0.653 AC: 99225 AN: 151996 Hom.: 32939 Cov.: 32 AF XY: 0.661 AC XY: 49133 AN XY: 74292

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.723

Gnomad4 ASJ AF: 0.579

Gnomad4 EAS AF: 0.910

Gnomad4 SAS AF: 0.643

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.639

Alfa AF: 0.657 Hom.: 79978

Bravo AF: 0.643

TwinsUK AF: 0.645 AC: 2393

ALSPAC AF: 0.668 AC: 2573

ESP6500AA AF: 0.553 AC: 2432

ESP6500EA AF: 0.657 AC: 5646

ExAC AF: 0.690 AC: 83753

Asia WGS AF: 0.764 AC: 2654 AN: 3478

EpiCase AF: 0.639

EpiControl AF: 0.643

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 88. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2021	Variant summary: CYBA c.214T>C (p.Tyr72His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.7 in 250626 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 1139 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYBA causing Chronic Granulomatous Disease phenotype (0.00061), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.214T>C in individuals affected with Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the clinical significance of this variant after 2014: four have classified the variant as benign and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30709874, 17383305, 21884584, 18799874, 19689263, 11023926, 15078863, 23821607, 22396743, 23409188, 25095657, 23040216, 9445163, 24339896, 24392120, 29132304, 29454792) -
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. -

Very early onset inflammatory bowel disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Institute of Clinical Molecular Biology, Kiel University

Nov 06, 2018

- -

CYBA POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Chronic granulomatous disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0000012	T
MutationTaster	Benign	0.046	P;P;P
PROVEAN	Uncertain	-4.0	D
ClinPred		0.063	T
GERP RS		3.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

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: rs4673; hg19: chr16-88713236; COSMIC: COSV55368224; COSMIC: COSV55368224;