22-41515801-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM5PP2BP4_StrongBS1_SupportingBS2
The NM_001098.3(ACO2):c.719G>C(p.Gly240Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,614,112 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G240S) has been classified as Pathogenic.
Frequency
Consequence
NM_001098.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000933 AC: 142AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000585 AC: 147AN: 251480Hom.: 0 AF XY: 0.000581 AC XY: 79AN XY: 135916
GnomAD4 exome AF: 0.000820 AC: 1198AN: 1461780Hom.: 2 Cov.: 32 AF XY: 0.000831 AC XY: 604AN XY: 727198
GnomAD4 genome AF: 0.000932 AC: 142AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:7
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Reported as a homozygous variant of uncertain significance in an individual with complex ataxia, pyramidal syndrome, and cerebellar atrophy; this individual did not have optic atrophy or retinal degeneration and had normal mitochondrial aconitase activity in fibroblasts (Marelli et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34056600, 32483926, 27528516, 30552426, 34354088, 32519519, 36294366) -
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This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 240 of the ACO2 protein (p.Gly240Ala). This variant is present in population databases (rs141878785, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with optic atrophy (PMID: 34056600). ClinVar contains an entry for this variant (Variation ID: 214018). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACO2 protein function with a negative predictive value of 80%. 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. -
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ACO2: PM2, PM3:Supporting, PM5:Supporting, PP3 -
Retinal dystrophy Uncertain:2
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Inborn genetic diseases Uncertain:1
The c.719G>C (p.G240A) alteration is located in exon 6 (coding exon 6) of the ACO2 gene. This alteration results from a G to C substitution at nucleotide position 719, causing the glycine (G) at amino acid position 240 to be replaced by an alanine (A). The in silico prediction for the p.G240A alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Mitochondrial disease Uncertain:1
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Infantile cerebellar-retinal degeneration;C4225384:Optic atrophy 9 Uncertain:1
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Optic atrophy 9 Uncertain:1
This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3. -
Infantile cerebellar-retinal degeneration Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at