rs147415774

chr1-183590217-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000433.4(NCF2):c.113G>A(p.Arg38Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0014 in 1,614,170 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.28

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]

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02710116).
• BP6: Variant 1-183590217-C-T is Benign according to our data. Variant chr1-183590217-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287151.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr1-183590217-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00145 (221/152278) while in subpopulation AMR AF= 0.00359 (55/15304). AF 95% confidence interval is 0.00284. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.113G>A	p.Arg38Gln	missense_variant	1/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.113G>A	p.Arg38Gln	missense_variant	1/15	1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00121 AC: 304 AN: 251480 Hom.: 1 AF XY: 0.00123 AC XY: 167 AN XY: 135912

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00140 AC: 2044 AN: 1461892 Hom.: 7 Cov.: 31 AF XY: 0.00135 AC XY: 980 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74448

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00153 Hom.: 1

Bravo AF: 0.00131

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00145 AC: 176

EpiCase AF: 0.000654

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 03, 2018	- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Uncertain:1 Benign:1

Uncertain significance, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 08, 2022

Variant summary: NCF2 c.113G>A (p.Arg38Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251480 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF2 causing Chronic Granulomatous Disease phenotype (0.00061), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.113G>A has been reported in the literature as associated with very early onset inflammatory bowel disease (IBD) and shown to reduce binding to RAC2 (example, Muise_2012). In recent reports, it continues to be cited among reported polymorphisms in the NCF2 gene (example, Roos_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, due to lack of penetrant association with inherited recessive Chronic Granulomatous Disease, the variant was classified as likely benign. -

NCF2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 03, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	0.77	D;D;D;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.033	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.35
MVP		0.85
MPC		1.1
ClinPred		0.18	T
GERP RS		5.0
Varity_R		0.65
gMVP		0.38

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: rs147415774; hg19: chr1-183559352;