1-183577660-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000433.4(NCF2):c.305G>A(p.Arg102Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NCF2
NM_000433.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.32

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-183577660-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF2	NM_000433.4 link	c.305G>A	p.Arg102Gln	missense_variant	Exon 3 of 15	ENST00000367535.8	NP_000424.2	P19878-1A0A0S2Z457

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8 link	c.305G>A	p.Arg102Gln	missense_variant	Exon 3 of 15	1	NM_000433.4	ENSP00000356505.4		P19878-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251492

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with primary immunodeficiency in published literature, however, a second NCF2 variant was not identified and variants were present in other genes associated with immunodeficiency (PMID: 30290665); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30290665) -

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

Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glutamine at codon 102 of the NCF2 protein (p.Arg102Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs137854515, ExAC 0.01%). This missense change has been observed in individual(s) with primary immunodeficiency disease (PMID: 30290665). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

Pathogenic

0.80

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;.;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;.;D

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

0.015

MutationAssessor

Pathogenic

3.3

M;M;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.66

Sift

Benign

0.036

D;D;D;D

Sift4G

Uncertain

0.013

D;T;T;T

Polyphen

0.88

.;.;P;P

Vest4

0.84

MutPred

0.71

Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);

MVP

0.87

MPC

0.78

ClinPred

0.87

GERP RS

5.7

Varity_R

0.72

gMVP

0.68

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