rs374402066
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000367535.8(NCF2):c.304C>T(p.Arg102Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000229 in 1,613,982 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
NCF2
ENST00000367535.8 stop_gained
ENST00000367535.8 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.99
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 Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-183577661-G-A is Pathogenic according to our data. Variant chr1-183577661-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2241.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-183577661-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NCF2 | NM_000433.4 | c.304C>T | p.Arg102Ter | stop_gained | 3/15 | ENST00000367535.8 | NP_000424.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NCF2 | ENST00000367535.8 | c.304C>T | p.Arg102Ter | stop_gained | 3/15 | 1 | NM_000433.4 | ENSP00000356505 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251488Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135916
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461818Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727228
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74320
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Arg102*) in the NCF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NCF2 are known to be pathogenic (PMID: 10498624, 20167518). This variant is present in population databases (rs374402066, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with chronic granulomatous disease (PMID: 10498624). ClinVar contains an entry for this variant (Variation ID: 2241). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at