NM_018075.5:c.132dupA

Variant names:

• chr3-43605720-C-CT
• rs540331226
• NM_018075.5:c.132dupA

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS1_Supporting

The NM_018075.5(ANO10):​c.132dupA​(p.Asp45ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,586,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: ANO10 NM_018075.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1
• Conservation: PhyloP100: 1.09
• Publications: 12 publications found

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: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-43605720-C-CT is Pathogenic according to our data. Variant chr3-43605720-C-CT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000698 (1002/1435164) while in subpopulation NFE AF = 0.000821 (897/1092100). AF 95% confidence interval is 0.000776. There are 0 homozygotes in GnomAdExome4. There are 484 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018075.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO10	NM_018075.5	MANE Select	c.132dupA	p.Asp45ArgfsTer9	frameshift	Exon 2 of 13	NP_060545.3
	ANO10	NM_001346464.2		c.132dupA	p.Asp45ArgfsTer9	frameshift	Exon 2 of 14	NP_001333393.1
	ANO10	NM_001346467.2		c.132dupA	p.Asp45ArgfsTer9	frameshift	Exon 2 of 14	NP_001333396.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO10	ENST00000292246.8	TSL:1 MANE Select	c.132dupA	p.Asp45ArgfsTer9	frameshift	Exon 2 of 13	ENSP00000292246.3	Q9NW15-1
	ANO10	ENST00000350459.8	TSL:1	c.132dupA	p.Asp45ArgfsTer9	frameshift	Exon 2 of 12	ENSP00000327767.4	Q9NW15-2
	ANO10	ENST00000970566.1		c.132dupA	p.Asp45ArgfsTer9	frameshift	Exon 2 of 15	ENSP00000640625.1

Frequencies

GnomAD3 genomes AF: 0.000450 AC: 68 AN: 151084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000724

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000327 AC: 76 AN: 232228 AF XY: 0.000367

Gnomad AFR exome AF: 0.000327

Gnomad AMR exome AF: 0.0000313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.000153

Gnomad NFE exome AF: 0.000550

Gnomad OTH exome AF: 0.000532

GnomAD4 exome AF: 0.000698 AC: 1002 AN: 1435164 Hom.: 0 Cov.: 32 AF XY: 0.000677 AC XY: 484 AN XY: 714436

African (AFR) AF: 0.000366 AC: 12 AN: 32796

American (AMR) AF: 0.00 AC: 0 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.000157 AC: 4 AN: 25478

East Asian (EAS) AF: 0.000182 AC: 7 AN: 38500

South Asian (SAS) AF: 0.0000701 AC: 6 AN: 85572

European-Finnish (FIN) AF: 0.000231 AC: 12 AN: 52024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.000821 AC: 897 AN: 1092100

Other (OTH) AF: 0.00109 AC: 64 AN: 58982

GnomAD4 genome AF: 0.000450 AC: 68 AN: 151200 Hom.: 0 Cov.: 32 AF XY: 0.000501 AC XY: 37 AN XY: 73898

African (AFR) AF: 0.000291 AC: 12 AN: 41292

American (AMR) AF: 0.0000659 AC: 1 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4784

European-Finnish (FIN) AF: 0.000288 AC: 3 AN: 10408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000725 AC: 49 AN: 67630

Other (OTH) AF: 0.000477 AC: 1 AN: 2096

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000385

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	1	-	Autosomal recessive spinocerebellar ataxia 10 (9)
8	-	-	not provided (8)
1	-	-	Abnormal central motor function (1)
1	-	-	Autosomal recessive cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs540331226; hg19: chr3-43647212; COSMIC: COSV52731618; COSMIC: COSV52731618;