18-12337454-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_006796.3(AFG3L2):c.2062C>G(p.Pro688Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P688S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006796.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AFG3L2 | NM_006796.3 | c.2062C>G | p.Pro688Ala | missense_variant | Exon 16 of 17 | ENST00000269143.8 | NP_006787.2 | |
AFG3L2 | XM_011525601.4 | c.1861C>G | p.Pro621Ala | missense_variant | Exon 15 of 16 | XP_011523903.1 | ||
LOC107985154 | XR_002958227.2 | n.3291+552G>C | intron_variant | Intron 1 of 1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:2
- -
Variant summary: AFG3L2 c.2062C>G (p.Pro688Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes. c.2062C>G has been reported in the literature as a heterozygous genotype in at-least three comprehensively genotyped and clinically evaluated individuals affected with Spinocerebellar Ataxia Type 28 (example, Sun_2019, Coutelier_2017). The variant segregated with disease in at-least one family reporting an affected mother and brother and inheritance from the affected mother to the affected proband with cerebellar atrophy and hyperreflexia, who underwent a comprehensive NGS based work up on a panel of 441 genes implicated in pure forms of cerebellar ataxia (Sun_2019). One of these individuals also displayed a T1-weighted sagittal and axial brain MRI showing slight vermian atrophy and underwent a NGS based workup on a panel of 65 genes involved in ataxia (Coutelier_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical cases supported by concrete functional studies are reported, the variant was classified as VUS-possibly pathogenic. -
not provided Uncertain:2
Previously reported in the heterozygous state in individuals with ataxia and/or cerebellar atrophy; however, familial segregation information was not reported (PMID: 28444220, 29915382, 35588347); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29915382, 35588347, 28444220) -
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at