rs767298430
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_StrongPM2BS1_Supporting
The NM_015697.9(COQ2):c.48dupC(p.Ala17ArgfsTer76) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000763 in 1,532,820 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000078 ( 1 hom. )
Consequence
COQ2
NM_015697.9 frameshift
NM_015697.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.488
Genes affected
COQ2 (HGNC:25223): (coenzyme Q2, polyprenyltransferase) This gene encodes an enzyme that functions in the final steps in the biosynthesis of CoQ (ubiquinone), a redox carrier in the mitochondrial respiratory chain and a lipid-soluble antioxidant. This enzyme, which is part of the coenzyme Q10 pathway, catalyzes the prenylation of parahydroxybenzoate with an all-trans polyprenyl group. Mutations in this gene cause coenzyme Q10 deficiency, a mitochondrial encephalomyopathy, and also COQ2 nephropathy, an inherited form of mitochondriopathy with primary renal involvement. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000657 (10/152230) while in subpopulation SAS AF= 0.00208 (10/4810). AF 95% confidence interval is 0.00113. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000173 AC: 24AN: 138354Hom.: 0 AF XY: 0.000240 AC XY: 18AN XY: 75148
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GnomAD4 exome AF: 0.0000775 AC: 107AN: 1380590Hom.: 1 Cov.: 33 AF XY: 0.000113 AC XY: 77AN XY: 681674
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GnomAD4 genome AF: 0.0000657 AC: 10AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74430
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 14, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29255295) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 12, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 235473). This variant has not been reported in the literature in individuals affected with COQ2-related conditions. This variant is present in population databases (rs767298430, gnomAD 0.1%). This sequence change creates a premature translational stop signal (p.Ala17Argfs*76) in the COQ2 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. - |
Focal segmental glomerulosclerosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 04, 2021 | - - |
Coenzyme Q10 deficiency, primary, 1;C3714927:Multiple system atrophy 1, susceptibility to Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 19, 2024 | - - |
Coenzyme Q10 deficiency, primary, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2023 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at