rs373386030
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_018075.5(ANO10):c.512T>C(p.Phe171Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,614,006 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. F171F) has been classified as Likely benign.
Frequency
Consequence
NM_018075.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANO10 | NM_018075.5 | c.512T>C | p.Phe171Ser | missense_variant | 5/13 | ENST00000292246.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANO10 | ENST00000292246.8 | c.512T>C | p.Phe171Ser | missense_variant | 5/13 | 1 | NM_018075.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251062Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135680
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727196
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 03, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2023 | Variant summary: ANO10 c.512T>C (p.Phe171Ser) 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 allele was found at a frequency of 2.8e-05 in 251062 control chromosomes (gnomAD). c.512T>C has been reported in the literature in individuals affected with cerebellar ataxia (Renaud_2014, Benkirane_2021), and one was reported as compound heterozygous with a (likely) pathogenic variant. 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. The following publications have been ascertained in the context of this evaluation (PMID: 25089919, 34234304). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 171 of the ANO10 protein (p.Phe171Ser). This variant is present in population databases (rs373386030, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of spinocerebellar ataxia (PMID: 25089919, 34234304). ClinVar contains an entry for this variant (Variation ID: 446836). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO10 protein function. Experimental studies have shown that this missense change affects ANO10 function (PMID: 32620747). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Autosomal recessive spinocerebellar ataxia 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 17, 2018 | The ANO10 c.512T>C (p.Phe171Ser) missense variant has been reported in a compound heterozygous state with a second frameshift variant in one individual affected with autosomal recessive cerebellar ataxia (Renaud M et al. 2014). Control data are unavailable for this variant. The p.Phe171Ser variant is reported at a frequency of 0.000063 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Phe171Ser variant is classified a variant of unknown significance but suspicious for pathogenicity for autosomal recessive spinocerebellar ataxia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at