3-43605720-CT-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018075.5(ANO10):​c.132delA​(p.Asp45MetfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000835 in 1,580,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: ANO10 NM_018075.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P: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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-43605720-CT-C is Pathogenic according to our data. Variant chr3-43605720-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2846174.Status of the report is criteria_provided_single_submitter, 1 stars.

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.132delA	p.Asp45MetfsTer12	frameshift	Exon 2 of 13	NP_060545.3
	ANO10	NM_001346464.2		c.132delA	p.Asp45MetfsTer12	frameshift	Exon 2 of 14	NP_001333393.1
	ANO10	NM_001346467.2		c.132delA	p.Asp45MetfsTer12	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.132delA	p.Asp45MetfsTer12	frameshift	Exon 2 of 13	ENSP00000292246.3	Q9NW15-1
	ANO10	ENST00000350459.8	TSL:1	c.132delA	p.Asp45MetfsTer12	frameshift	Exon 2 of 12	ENSP00000327767.4	Q9NW15-2
	ANO10	ENST00000970566.1		c.132delA	p.Asp45MetfsTer12	frameshift	Exon 2 of 15	ENSP00000640625.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 151072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000474 AC: 11 AN: 232228 AF XY: 0.0000479

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000588

Gnomad FIN exome AF: 0.000254

Gnomad NFE exome AF: 0.0000474

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000903 AC: 129 AN: 1429308 Hom.: 0 Cov.: 32 AF XY: 0.0000928 AC XY: 66 AN XY: 711472

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000306 AC: 1 AN: 32682

American (AMR) AF: 0.0000228 AC: 1 AN: 43866

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 4 AN: 25340

East Asian (EAS) AF: 0.000157 AC: 6 AN: 38210

South Asian (SAS) AF: 0.0000820 AC: 7 AN: 85346

European-Finnish (FIN) AF: 0.000310 AC: 16 AN: 51648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.0000809 AC: 88 AN: 1087958

Other (OTH) AF: 0.000102 AC: 6 AN: 58606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 151072 Hom.: 0 Cov.: 32 AF XY: 0.0000407 AC XY: 3 AN XY: 73766

African (AFR) AF: 0.00 AC: 0 AN: 41160

American (AMR) AF: 0.00 AC: 0 AN: 15156

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67636

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00182 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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: COSV52728949; COSMIC: COSV52728949;