rs796065033
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_000433.4(NCF2):c.55_63delAAGAAGGAC(p.Lys19_Asp21del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000186 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K19K) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NCF2
NM_000433.4 conservative_inframe_deletion
NM_000433.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.04
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.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000433.4.
PP5
Variant 1-183590266-AGTCCTTCTT-A is Pathogenic according to our data. Variant chr1-183590266-AGTCCTTCTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 2245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NCF2 | NM_000433.4 | c.55_63delAAGAAGGAC | p.Lys19_Asp21del | conservative_inframe_deletion | Exon 1 of 15 | ENST00000367535.8 | NP_000424.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727248
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GnomAD4 genome 0.0000131 AC: 2AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
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 26, 2024 | This variant, c.55_63del, results in the deletion of 3 amino acid(s) of the NCF2 protein (p.Lys19_Asp21del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs796065033, gnomAD 0.003%). This variant has been observed in individual(s) with chronic granulomatous disease (PMID: 10498624, 10598813, 18625437; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2245). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 27, 2019 | In-frame deletion of 3 amino acids in a non-repeat region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18625437, 20167518, 10598813, 10498624, 32040803) - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at