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GeneBe

rs13306581

Variant summary

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

The NM_000433.4(NCF2):c.836C>T(p.Thr279Met) variant causes a missense change. The variant allele was found at a frequency of 0.00122 in 1,614,094 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T279T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 26 hom. )

Consequence

NCF2
NM_000433.4 missense

Scores

2
7
7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.62
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010832995).
BP6
Variant 1-183567223-G-A is Benign according to our data. Variant chr1-183567223-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 379274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183567223-G-A is described in Lovd as [Benign]. Variant chr1-183567223-G-A is described in Lovd as [Likely_benign]. Variant chr1-183567223-G-A is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00134 (204/152208) while in subpopulation EAS AF= 0.0267 (138/5178). AF 95% confidence interval is 0.023. There are 1 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NCF2NM_000433.4 linkuse as main transcriptc.836C>T p.Thr279Met missense_variant 8/15 ENST00000367535.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NCF2ENST00000367535.8 linkuse as main transcriptc.836C>T p.Thr279Met missense_variant 8/151 NM_000433.4 P1P19878-1

Frequencies

GnomAD3 genomes
AF:
0.00135
AC:
206
AN:
152090
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.0154
Gnomad AMR
AF:
0.000590
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.0270
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000323
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.00216
AC:
541
AN:
250720
Hom.:
7
AF XY:
0.00196
AC XY:
266
AN XY:
135500
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00468
Gnomad EAS exome
AF:
0.0226
Gnomad SAS exome
AF:
0.000719
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000309
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.00121
AC:
1762
AN:
1461886
Hom.:
26
Cov.:
32
AF XY:
0.00123
AC XY:
897
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00398
Gnomad4 EAS exome
AF:
0.0288
Gnomad4 SAS exome
AF:
0.000812
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.000254
Gnomad4 OTH exome
AF:
0.00225
GnomAD4 genome
AF:
0.00134
AC:
204
AN:
152208
Hom.:
1
Cov.:
32
AF XY:
0.00159
AC XY:
118
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000589
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.0267
Gnomad4 SAS
AF:
0.00187
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00112
Hom.:
2
Bravo
AF:
0.00119
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.00228
AC:
277
Asia WGS
AF:
0.0210
AC:
72
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022NCF2: BS1, BS2 -
Benign, criteria provided, single submitterclinical testingGeneDxMay 05, 2020This variant is associated with the following publications: (PMID: 29560547, 31180159) -
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 18, 2022- -
NCF2-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 09, 2019This 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
Benign
0.11
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.28
Cadd
Pathogenic
30
Dann
Pathogenic
1.0
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D;.;D;D
MetaRNN
Benign
0.011
T;T;T;T;T
MetaSVM
Benign
-0.75
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D
REVEL
Benign
0.22
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;.
Polyphen
1.0
.;.;D;D;.
Vest4
0.50
MVP
0.79
MPC
1.1
ClinPred
0.065
T
GERP RS
5.4
Varity_R
0.51
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs13306581; hg19: chr1-183536358; COSMIC: COSV62315646; COSMIC: COSV62315646; API