chr3-43576874-T-C
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_018075.5(ANO10):āc.980A>Gā(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: š 0.0035 ( 0 hom., cov: 32)
Exomes š: 0.0048 ( 23 hom. )
Consequence
ANO10
NM_018075.5 missense
NM_018075.5 missense
Scores
6
13
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 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: {Likely_benign=3, Uncertain_significance=5}. 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.
BS2
High Homozygotes in GnomAdExome4 at 23 AR gene
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: 535AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00323 AC: 812AN: 251306Hom.: 0 AF XY: 0.00319 AC XY: 433AN XY: 135812
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GnomAD4 exome AF: 0.00480 AC: 7010AN: 1461878Hom.: 23 Cov.: 32 AF XY: 0.00469 AC XY: 3411AN XY: 727238
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GnomAD4 genome AF: 0.00351 AC: 535AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.00313 AC XY: 233AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:2
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 | Athena Diagnostics | Jun 15, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
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:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 29, 2016 | - - |
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, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;.;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at