rs138000380

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

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

Clinical Significance

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

Conservation

PhyloP100: 7.15

Publications

19 publications found

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]

ANO10 Gene-Disease associations (from GenCC):

autosomal recessive spinocerebellar ataxia 10
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ANO10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2106108).

BP6

Variant 3-43432682-C-T is Benign according to our data. Variant chr3-43432682-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162017.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO10	NM_018075.5 link	c.1843G>A	p.Asp615Asn	missense_variant	Exon 12 of 13	ENST00000292246.8	NP_060545.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO10	ENST00000292246.8 link	c.1843G>A	p.Asp615Asn	missense_variant	Exon 12 of 13	1	NM_018075.5	ENSP00000292246.3

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152122

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000407

AC:

102

AN:

250800

AF XY:

0.000428

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 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.:

Cov.:

AF XY:

0.000499

AC XY:

363

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00532

AC:

139

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000490

AC:

545

AN:

1111890

Other (OTH)

AF:

0.000679

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000388

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41550

American (AMR)

AF:

0.000327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000524

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000346

AC:

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

- -

Nov 01, 2014

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

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. -

not specified

Uncertain:2Benign:1

Jul 31, 2024

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. Four of five 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 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ANO10 causing Spinocerebellar ataxia 10 (0.00041 vs 0.0011), allowing no conclusion about variant significance. 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. This study showed that 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. The following publications have been ascertained in the context of this evaluation (PMID: 25182700, 31477691, 25976027). ClinVar contains an entry for this variant (Variation ID: 162017). 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. -

Feb 14, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:1

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 -

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

0.053

MutationAssessor

Pathogenic

3.5

H;.;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.51

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

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.82

gMVP

0.86

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over