ClinVar Genomic variation as it relates to human health
NM_018075.5(ANO10):c.1843G>A (p.Asp615Asn)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018075.5(ANO10):c.1843G>A (p.Asp615Asn)
Variation ID: 162017 Accession: VCV000162017.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.1 3: 43432682 (GRCh38) [ NCBI UCSC ] 3: 43474174 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 18, 2015 Apr 15, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018075.5:c.1843G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060545.3:p.Asp615Asn missense NM_001204831.3:c.1798-59835G>A intron variant NM_001204832.3:c.1645G>A NP_001191761.1:p.Asp549Asn missense NM_001204833.3:c.1510G>A NP_001191762.1:p.Asp504Asn missense NM_001204834.3:c.1273G>A NP_001191763.1:p.Asp425Asn missense NM_001346463.2:c.1915-65708G>A intron variant NM_001346464.2:c.1960G>A NP_001333393.1:p.Asp654Asn missense NM_001346465.2:c.1798-65708G>A intron variant NM_001346466.2:c.1645G>A NP_001333395.1:p.Asp549Asn missense NM_001346467.2:c.1960G>A NP_001333396.1:p.Asp654Asn missense NM_001346468.2:c.1843G>A NP_001333397.1:p.Asp615Asn missense NM_001346469.2:c.1645G>A NP_001333398.1:p.Asp549Asn missense NC_000003.12:g.43432682C>T NC_000003.11:g.43474174C>T NG_028216.2:g.263913G>A - Protein change
- D615N, D425N, D654N, D504N, D549N
- Other names
- ANO10, ASP615ASN (rs138000380)
- Canonical SPDI
- NC_000003.12:43432681:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00080 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00035
Trans-Omics for Precision Medicine (TOPMed) 0.00034
The Genome Aggregation Database (gnomAD) 0.00035
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD), exomes 0.00041
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ANO10 | - | - |
GRCh38 GRCh37 |
441 | 505 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2022 | RCV000149438.24 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 18, 2022 | RCV001815207.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 21, 2024 | RCV002514864.13 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000593206.3
First in ClinVar: Oct 11, 2015 Last updated: Jan 29, 2022 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Oct 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600560.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive spinocerebellar ataxia 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002799679.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive spinocerebellar ataxia 10
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915332.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Likely benign
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003282102.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
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Uncertain significance
(Dec 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004154315.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
ANO10: PM2:Supporting, PM3:Supporting
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Spinocerebellar ataxia, autosomal recessive 10
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142328.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Nov 01, 2014)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000196076.3
First in ClinVar: Dec 20, 2014 Last updated: Jan 08, 2022 |
Comment on evidence:
This variant, formerly titled SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 10, has been reclassified because of inconsistencies and/or errors in the numbering of variants based on the … (more)
This variant, formerly titled SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 10, has been reclassified because of inconsistencies and/or errors in the numbering of variants based on the cited reference sequence in the article by Balreira et al. (2014). For discussion of the asp615-to-asn (D615N) mutation in the ANO10 gene that was found in compound heterozygous state in a patient with autosomal recessive spinocerebellar ataxia-10 (SCAR10; 613728) by Balreira et al. (2014), see 613726.0005. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. | Bushell SR | Nature communications | 2019 | PMID: 31477691 |
Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia. | Keogh MJ | Journal of neurology | 2015 | PMID: 25976027 |
ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency. | Balreira A | Journal of neurology | 2014 | PMID: 25182700 |
Text-mined citations for rs138000380 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.