chr22-41527949-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5
The NM_001098.3(ACO2):c.2135C>T(p.Pro712Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,614,072 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P712P) has been classified as Likely benign.
Frequency
Consequence
NM_001098.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACO2 | NM_001098.3 | c.2135C>T | p.Pro712Leu | missense_variant | 17/18 | ENST00000216254.9 | |
POLR3H | NM_001018050.4 | c.*1334G>A | 3_prime_UTR_variant | 6/6 | ENST00000355209.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACO2 | ENST00000216254.9 | c.2135C>T | p.Pro712Leu | missense_variant | 17/18 | 1 | NM_001098.3 | P3 | |
POLR3H | ENST00000355209.9 | c.*1334G>A | 3_prime_UTR_variant | 6/6 | 1 | NM_001018050.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250696Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135520
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727244
GnomAD4 genome AF: 0.000125 AC: 19AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74350
ClinVar
Submissions by phenotype
Infantile cerebellar-retinal degeneration Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 19, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 14, 2013 | Likely pathogenicity based on finding it once in trans with another missense variant (R607C) in a 2-year-old male with global delays, bilateral sensorineural hearing loss, hypotonia, ataxia, myclonic jerks, dysmorphisms, small arachnoid cyst. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 712 of the ACO2 protein (p.Pro712Leu). This variant is present in population databases (rs375761361, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of infantile cerebellar-retinal degeneration (PMID: 26992325, 29564393). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218317). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACO2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2021 | Published functional studies demonstrate a damaging effect on ACO2 enzyme activity (Sadat 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: 32519519, 26992325, 31106992, 29564393, 32713659, 33028849, 31589614) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2024 | Variant summary: ACO2 c.2135C>T (p.Pro712Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250696 control chromosomes. c.2135C>T has been reported in the literature in multiple compound heterozygous individuals affected with infantile cerebellar-retinal degeneration or optic atrophy with spastic paraplegia (e.g. Sadat_2016, Marelli_2018). These data indicate that the variant may be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, showing reduced enzyme activity in patient fibroblasts from compound heterozygous individuals, however, none of these studies allows convincing conclusions about the variant effect (e.g. Sadat_2016, Marelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29564393, 26992325). ClinVar contains an entry for this variant (Variation ID: 218317). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at