chr22-41469180-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3PP5_Moderate
The NM_001098.3(ACO2):c.34C>T(p.Gln12Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,455,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q12Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001098.3 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACO2 | NM_001098.3 | c.34C>T | p.Gln12Ter | stop_gained, splice_region_variant | 1/18 | ENST00000216254.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACO2 | ENST00000216254.9 | c.34C>T | p.Gln12Ter | stop_gained, splice_region_variant | 1/18 | 1 | NM_001098.3 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455152Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723874
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2015 | The Q12X pathogenic variant in the ACO2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q12X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A protein truncating variant downstream of this variant has been reported in an individual with isolated optic atrophy in the Human Gene Mutation Database (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. We interpret Q12X as a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at