rs147415774
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
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
Consequence
NM_000433.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
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: 221AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00121 AC: 304AN: 251480Hom.: 1 AF XY: 0.00123 AC XY: 167AN XY: 135912
GnomAD4 exome AF: 0.00140 AC: 2044AN: 1461892Hom.: 7 Cov.: 31 AF XY: 0.00135 AC XY: 980AN XY: 727246
GnomAD4 genome ? AF: 0.00145 AC: 221AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 03, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2021 | - - |
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
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. - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at