rs758937084
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018075.5(ANO10):βc.96delβ(p.Glu33AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.000086 ( 0 hom., cov: 32)
Exomes π: 0.00019 ( 0 hom. )
Consequence
ANO10
NM_018075.5 frameshift
NM_018075.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.51
Genes affected
ANO10 (HGNC:25519): (anoctamin 10) The transmembrane protein encoded by this gene belongs to the anoctamin family of calcium-activated chloride channels, also known as the transmembrane 16 family. The encoded protein contains eight transmembrane domains with cytosolic N- and C-termini. Defects in this gene may cause autosomal recessive spinocerebellar ataxia-10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 3-43605756-CT-C is Pathogenic according to our data. Variant chr3-43605756-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 434215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANO10 | NM_018075.5 | c.96del | p.Glu33AsnfsTer3 | frameshift_variant | 2/13 | ENST00000292246.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANO10 | ENST00000292246.8 | c.96del | p.Glu33AsnfsTer3 | frameshift_variant | 2/13 | 1 | NM_018075.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152034Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251248Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135788
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GnomAD4 exome AF: 0.000192 AC: 280AN: 1461534Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 146AN XY: 727054
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GnomAD4 genome ? AF: 0.0000855 AC: 13AN: 152034Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74260
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Glu33Asnfs*3) in the ANO10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO10 are known to be pathogenic (PMID: 25089919). This variant is present in population databases (rs758937084, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive spinocerebellar ataxia, (PMID: 29915382, 32816195). ClinVar contains an entry for this variant (Variation ID: 434215). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ANO10: PVS1, PM3:Strong, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29915382, 31589614) - |
Autosomal recessive spinocerebellar ataxia 10 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 26, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 13). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. More than 5 NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar and PMIDs: 29915382, 21092923). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a patient with ataxia (PMID: 29915382) and as pathogenic in ClinVar. (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000434215 / PMID: 29915382). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at