NM_018075.5:c.1843G>A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_018075.5(ANO10):c.1843G>A(p.Asp615Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000492 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_018075.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANO10 | NM_018075.5 | c.1843G>A | p.Asp615Asn | missense_variant | Exon 12 of 13 | ENST00000292246.8 | NP_060545.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000388 AC: 59AN: 152122Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000407 AC: 102AN: 250800Hom.: 0 AF XY: 0.000428 AC XY: 58AN XY: 135536
GnomAD4 exome AF: 0.000503 AC: 735AN: 1461664Hom.: 0 Cov.: 31 AF XY: 0.000499 AC XY: 363AN XY: 727146
GnomAD4 genome AF: 0.000388 AC: 59AN: 152240Hom.: 0 Cov.: 31 AF XY: 0.000430 AC XY: 32AN XY: 74410
ClinVar
Submissions by phenotype
Autosomal recessive spinocerebellar ataxia 10 Pathogenic:1Uncertain:3
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NM_018075.3:c.1843G>A in the ANO10 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Considering the adult-onset, the global allele frequency is 0.0003792 and no homozygous was observed in the gnomAD database, we applied PM2. In addition, this missense variant has been reported in one study in which it is identified in one individual with adult-onset spinocerebellar ataxia in a compound heterozygous state with a frameshift variant (PMID25182700). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PP3; PM3; PP4; PM2. -
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The ANO10 c.1843G>A (p.Asp615Asn) missense variant has been reported in one study in which it is identified in one individual with adult-onset spinocerebellar ataxia in a compound heterozygous state with a frameshift variant (Balreira et al. 2014). The p.Asp615Asn was absent from the healthy brother and is reported at a frequency of 0.00533 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the limited clinical evidence, the p.Asp615Asn variant is considered to be 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. -
not specified Uncertain:2Benign:1
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Variant summary: ANO10 c.1843G>A (p.Asp615Asn) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 250800 control chromosomes, predominantly at a frequency of 0.0055 within the Ashkenazi Jewish subpopulation in the gnomAD database. c.1843G>A has been reported in the literature as a compound heterozygous genotype together with a frameshift variant in an individual affected with Autosomal Recessive Spinocerebellar Ataxia (Balreira_2014). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. It found that the variant did not alter lipid scrambling compared to the wild-type protein in the presence or the absence of calcium (Bushell_2019); however, this does not allow convincing conclusions about the variant effect. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as VUS and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -
DNA sequence analysis of the ANO10 gene demonstrated a sequence change, c.1843G>A, in exon 12 that results in an amino acid change, p.Asp615Asn. The p.Asp615Asn change affects a moderately conserved amino acid residue located in a domain of the ANO10 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp615Asn substitution. This particular amino acid change has been described in the literature in the compound heterozygous state with a pathogenic frameshift ANO10 variant in a patient with ataxia (Balreira et al., 2014). This sequence change has been described in the gnomAD database with a frequency of 0.55% in the Ashkenazi Jewish subpopulation (dbSNP rs138000380). Due to the high allele frequency in the gnomAD population database and the lack of functional studies, the p.Asp615Asn variant is interpreted as a variant of unknown significance. -
not provided Uncertain:2Benign:1
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ANO10: PM2:Supporting, PM3:Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at