1-183563301-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5 BP4_Strong BP6 BS1

The NM_000433.4(NCF2):c.1184G>A(p.Arg395Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R395W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.481

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 -7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-183563302-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.013055384).
• BP6: Variant 1-183563301-C-T is Benign according to our data. Variant chr1-183563301-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294080.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr1-183563301-C-T is described in Lovd as [Likely_benign]. Variant chr1-183563301-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00123 (187/152242) while in subpopulation NFE AF= 0.00206 (140/68018). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.1184G>A	p.Arg395Gln	missense_variant	13/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.1184G>A	p.Arg395Gln	missense_variant	13/15	1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00114 AC: 286 AN: 251366 Hom.: 0 AF XY: 0.00113 AC XY: 153 AN XY: 135860

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00181 AC: 2642 AN: 1461808 Hom.: 3 Cov.: 32 AF XY: 0.00178 AC XY: 1294 AN XY: 727206

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00226

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74440

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00125

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00106 AC: 129

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 13, 2022	This variant has been reported in association with Crohn's disease and inflammatory bowel disease (Denson 2018 PMID: 29454792; Ashton 2020 PMID: 32463623). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.2% [140/68026]; https://gnomad.broadinstitute.org/variant/1-183563301-C-T?dataset=gnomad_r3). It is also present in ClinVar, with several laboratories classifying it as benign or likely benign (Variation ID: 2248). Evolutionary conservation and computational predictive tools strongly suggest that this variant does not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

NCF2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 08, 2023

The NCF2 c.1184G>A variant is predicted to result in the amino acid substitution p.Arg395Gln. This variant has been reported in association with inflammatory bowel disease (Table 1, Denson et al. 2018. PubMed ID: 29454792; Table 2, Ashton et al. 2020. PubMed ID: 32463623). However, this variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-183532436-C-T), which may be too high to be causative. This variant also has conflicting interpretations regarding its pathogenic in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/294080/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.85	T;T;.;D;D;D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;N;N;N;D;N
REVEL	Benign	0.0090
Sift	Benign	0.19	T;T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;.;.
Polyphen		0.034	.;.;B;B;.;.
Vest4		0.10
MVP		0.48
MPC		0.40
ClinPred		0.011	T
GERP RS		2.7
Varity_R		0.32
gMVP		0.39

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

Other links and lift over

dbSNP: rs145229115; hg19: chr1-183532436; COSMIC: COSV62314951;