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

Genomes: 𝑓 0.00039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

ANO10
NM_018075.5 missense

Scores

6
8
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:2

Conservation

PhyloP100: 7.15
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2106108).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANO10NM_018075.5 linkc.1843G>A p.Asp615Asn missense_variant Exon 12 of 13 ENST00000292246.8 NP_060545.3 Q9NW15-1A0A024R2S0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANO10ENST00000292246.8 linkc.1843G>A p.Asp615Asn missense_variant Exon 12 of 13 1 NM_018075.5 ENSP00000292246.3 Q9NW15-1

Frequencies

GnomAD3 genomes
AF:
0.000388
AC:
59
AN:
152122
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000500
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000407
AC:
102
AN:
250800
Hom.:
0
AF XY:
0.000428
AC XY:
58
AN XY:
135536
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00547
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000344
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000503
AC:
735
AN:
1461664
Hom.:
0
Cov.:
31
AF XY:
0.000499
AC XY:
363
AN XY:
727146
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00532
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.000490
Gnomad4 OTH exome
AF:
0.000679
GnomAD4 genome
AF:
0.000388
AC:
59
AN:
152240
Hom.:
0
Cov.:
31
AF XY:
0.000430
AC XY:
32
AN XY:
74410
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00490
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.000500
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000552
Hom.:
0
Bravo
AF:
0.000336
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000346
AC:
42
EpiCase
AF:
0.000545
EpiControl
AF:
0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 10 Pathogenic:1Uncertain:3
Mar 30, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

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. -

Nov 01, 2014
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Oct 18, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 14, 2024
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 18, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Apr 21, 2021
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Mar 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Dec 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ANO10: PM2:Supporting, PM3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.24
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.31
T;.;.;.
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.21
T;T;T;T
MetaSVM
Uncertain
0.053
D
MutationAssessor
Pathogenic
3.5
H;.;.;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-4.6
D;D;D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0040
D;D;D;D
Sift4G
Uncertain
0.012
D;D;D;D
Polyphen
0.81
P;P;P;P
Vest4
0.94
MVP
0.77
MPC
0.37
ClinPred
0.89
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1
Varity_R
0.82
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138000380; hg19: chr3-43474174; API