16-88646828-A-G

Variant names:

• chr16-88646828-A-G
• rs4673
• NM_000101.4:c.214T>C

Variant summary

Our verdict is Benign. The variant received -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:13 O:1
• Conservation: PhyloP100: 4.22
• Publications: 401 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: Benign. The variant received -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 VariationId is 2263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CYBA	NM_000101.4	c.214T>C	p.Tyr72His	missense_variant	Exon 4 of 6	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4	c.214T>C	p.Tyr72His	missense_variant	Exon 4 of 6		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8	c.214T>C	p.Tyr72His	missense_variant	Exon 4 of 6	1	NM_000101.4	ENSP00000261623.3

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

GnomAD2 exomes AF: 0.698 AC: 174863 AN: 250626 AF XY: 0.690

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 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

African (AFR) AF: 0.541 AC: 18100 AN: 33440

American (AMR) AF: 0.760 AC: 33973 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 15147 AN: 26122

East Asian (EAS) AF: 0.906 AC: 35974 AN: 39686

South Asian (SAS) AF: 0.634 AC: 54683 AN: 86226

European-Finnish (FIN) AF: 0.813 AC: 43211 AN: 53176

Middle Eastern (MID) AF: 0.570 AC: 3288 AN: 5766

European-Non Finnish (NFE) AF: 0.665 AC: 739154 AN: 1110744

Other (OTH) AF: 0.666 AC: 40171 AN: 60336

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

African (AFR) AF: 0.543 AC: 22498 AN: 41424

American (AMR) AF: 0.723 AC: 11043 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2007 AN: 3468

East Asian (EAS) AF: 0.910 AC: 4702 AN: 5166

South Asian (SAS) AF: 0.643 AC: 3100 AN: 4822

European-Finnish (FIN) AF: 0.824 AC: 8724 AN: 10592

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 45011 AN: 67926

Other (OTH) AF: 0.639 AC: 1350 AN: 2114

Alfa AF: 0.657 Hom.: 159400

Bravo AF: 0.643

TwinsUK AF: 0.645 AC: 2393

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:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 16, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Benign:4

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Very early onset inflammatory bowel disease Pathogenic:1

Nov 06, 2018

Institute of Clinical Molecular Biology, Kiel University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Chronic granulomatous disease Benign:1

Nov 18, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

CYBA POLYMORPHISM Benign:1

Jul 01, 2009

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

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
MetaRNN	Benign	0.0000012	T
PhyloP100		4.2
PROVEAN	Uncertain	-4.0	D
ClinPred		0.063	T
GERP RS		3.5
PromoterAI		0.27	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.19
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

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