rs146569520

chr3-43576874-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_018075.5(ANO10):c.980A>G(p.Tyr327Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00467 in 1,614,140 control chromosomes in the GnomAD database, including 23 homozygotes. 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 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (23 hom.)
• Consequence: ANO10 NM_018075.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 4.21

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009207547).
• BP6: Variant 3-43576874-T-C is Benign according to our data. Variant chr3-43576874-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345189.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3}. Variant chr3-43576874-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00351 (535/152262) while in subpopulation NFE AF= 0.00582 (396/68036). AF 95% confidence interval is 0.00535. There are 0 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO10	NM_018075.5	c.980A>G	p.Tyr327Cys	missense_variant	6/13	ENST00000292246.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO10	ENST00000292246.8	c.980A>G	p.Tyr327Cys	missense_variant	6/13	1	NM_018075.5	P1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00323 AC: 812 AN: 251306 Hom.: 0 AF XY: 0.00319 AC XY: 433 AN XY: 135812

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00506

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00480 AC: 7010 AN: 1461878 Hom.: 23 Cov.: 32 AF XY: 0.00469 AC XY: 3411 AN XY: 727238

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.00363

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00565

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.00351 AC: 535 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74450

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00582

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00528 Hom.: 4

Bravo AF: 0.00403

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00333 AC: 404

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2023	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2016	The Y327C variant in the ANO10 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports Y327C was observed in 60/8600 (0.7%) alleles from individuals of European American background, indicating it may be a rare variant in this population. The Y327C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Y327C as a variant of uncertain significance. -

Autosomal recessive spinocerebellar ataxia 10 Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 29, 2016	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.980A>G (p.Y327C) alteration is located in exon 6 (coding exon 5) of the ANO10 gene. This alteration results from a A to G substitution at nucleotide position 980, causing the tyrosine (Y) at amino acid position 327 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.061	T;.;.;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0092	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0030	B;B;.;B
Vest4		0.52
MVP		0.59
MPC		0.13
ClinPred		0.022	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs146569520; hg19: chr3-43618366; COSMIC: COSV52732808; COSMIC: COSV52732808;