rs562308643

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_000101.4(CYBA):c.395C>T(p.Thr132Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,534,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CYBA
NM_000101.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.0780

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03098157).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000171 (26/152174) while in subpopulation AFR AF= 0.000553 (23/41556). AF 95% confidence interval is 0.000378. There are 0 homozygotes in gnomad4. There are 14 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYBA	NM_000101.4 linkuse as main transcript	c.395C>T	p.Thr132Met	missense_variant	6/6	ENST00000261623.8	NP_000092.2
CYBA	XM_011522905.4 linkuse as main transcript	c.*1620C>T		3_prime_UTR_variant	6/6		XP_011521207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYBA	ENST00000261623.8 linkuse as main transcript	c.395C>T	p.Thr132Met	missense_variant	6/6	1	NM_000101.4	ENSP00000261623	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000456

AC:

AN:

131492

Hom.:

AF XY:

0.0000277

AC XY:

AN XY:

72140

show subpopulations

Gnomad AFR exome

AF:

0.000311

Gnomad AMR exome

AF:

0.0000409

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:

0.0000614

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000289

AC:

AN:

1382488

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

682578

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

Gnomad4 AMR exome

AF:

0.0000840

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000167

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000288

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000171

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000364

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3466

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.395C>T (p.T132M) alteration is located in exon 6 (coding exon 6) of the CYBA gene. This alteration results from a C to T substitution at nucleotide position 395, causing the threonine (T) at amino acid position 132 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Chronic granulomatous disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 132 of the CYBA protein (p.Thr132Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 567401). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.47

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.72

M_CAP

Benign

0.077

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

REVEL

Benign

0.22

Sift

Benign

0.11

Sift4G

Benign

0.099

Polyphen

0.065

Vest4

0.089

MutPred

0.29

Gain of catalytic residue at T132 (P = 0.024);

MVP

0.62

MPC

0.18

ClinPred

0.0097

GERP RS

-5.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.020

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over