rs138000380

Positions:

• chr3-43432682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1
• Conservation: PhyloP100: 7.15

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]

ACMG classification

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/exons	MANE	Protein	UniProt
ANO10	NM_018075.5	c.1843G>A	p.Asp615Asn	missense_variant	12/13	ENST00000292246.8	NP_060545.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO10	ENST00000292246.8	c.1843G>A	p.Asp615Asn	missense_variant	12/13	1	NM_018075.5	ENSP00000292246.3

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152122 Hom.: 0 Cov.: 31

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

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

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

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:1 Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 10 Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2017	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. -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	ANO10: PM2:Supporting, PM3:Supporting -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 21, 2021	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. -

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

Other links and lift over

dbSNP: rs138000380; hg19: chr3-43474174;