chr1-183563229-T-A

Position:

chr1-183563229-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000433.4(NCF2):c.1256A>T(p.Asn419Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 1,614,052 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N419Y) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 72 hom. )

Consequence

NCF2
NM_000433.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

NCF2 (HGNC:7661): (neutrophil cytosolic factor 2) This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein NADPH oxidase complex found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease, a disease that causes recurrent infections by catalase-positive organisms. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

NCF2 links:

SMG7 (HGNC:16792): (SMG7 nonsense mediated mRNA decay factor) This gene encodes a protein that is essential for nonsense-mediated mRNA decay (NMD); a process whereby transcripts with premature termination codons are targeted for rapid degradation by a mRNA decay complex. The mRNA decay complex consists, in part, of this protein along with proteins SMG5 and UPF1. The N-terminal domain of this protein is thought to mediate its association with SMG5 or UPF1 while the C-terminal domain interacts with the mRNA decay complex. This protein may therefore couple changes in UPF1 phosphorylation state to the degradation of NMD-candidate transcripts. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

SMG7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0100801885).

BP6

Variant 1-183563229-T-A is Benign according to our data. Variant chr1-183563229-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 281211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183563229-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00537 (817/152190) while in subpopulation SAS AF= 0.00973 (47/4828). AF 95% confidence interval is 0.00791. There are 6 homozygotes in gnomad4. There are 374 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF2	NM_000433.4 linkuse as main transcript	c.1256A>T	p.Asn419Ile	missense_variant	13/15	ENST00000367535.8	NP_000424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8 linkuse as main transcript	c.1256A>T	p.Asn419Ile	missense_variant	13/15	1	NM_000433.4	ENSP00000356505	P1	P19878-1

Frequencies

GnomAD3 genomes

AF:

0.00537

AC:

817

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00973

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00848

Gnomad OTH

AF:

0.00767

GnomAD3 exomes

AF:

0.00552

AC:

1387

AN:

251352

Hom.:

AF XY:

0.00573

AC XY:

778

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.00575

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00675

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00821

AC:

12000

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

5956

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00449

Gnomad4 ASJ exome

AF:

0.00570

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0106

Gnomad4 FIN exome

AF:

0.00161

Gnomad4 NFE exome

AF:

0.00898

Gnomad4 OTH exome

AF:

0.00952

GnomAD4 genome

AF:

0.00537

AC:

817

AN:

152190

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

374

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00174

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00973

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00849

Gnomad4 OTH

AF:

0.00759

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.00550

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00872

AC:

ExAC

AF:

0.00537

AC:

652

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00905

EpiControl

AF:

0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NCF2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2020	This variant is associated with the following publications: (PMID: 23821607, 16937026, 27884173, 26764160, 27535533, 29454792, 24931457) -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Developmental and epileptic encephalopathy, 28

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The homozygous p.Asn419Ile variant in NCF2 has been identified in a Tunisian individual with chronic granulomatous disease (PMID: 16937026), individuals without chronic granulomatous disease (PMID: 23821607), and has been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive chronic granulomatous disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

.;.;T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

D;D;.;D

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.7

.;.;M;M

MutationTaster

Benign

0.52

D;N;N;N

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

0.99

.;.;D;D

Vest4

0.46

MVP

0.70

MPC

0.80

ClinPred

0.034

GERP RS

4.5

Varity_R

0.89

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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