rs200631556
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_213599.3(ANO5):āc.2141C>Gā(p.Thr714Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,614,064 control chromosomes in the GnomAD database, including 4 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 0.00090 ( 0 hom., cov: 32)
Exomes š: 0.00078 ( 4 hom. )
Consequence
ANO5
NM_213599.3 missense
NM_213599.3 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.19104081).
BS2
High AC in GnomAd4 at 137 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANO5 | NM_213599.3 | c.2141C>G | p.Thr714Ser | missense_variant | 19/22 | ENST00000324559.9 | NP_998764.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ANO5 | ENST00000324559.9 | c.2141C>G | p.Thr714Ser | missense_variant | 19/22 | 1 | NM_213599.3 | ENSP00000315371 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000901 AC: 137AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000887 AC: 223AN: 251442Hom.: 1 AF XY: 0.000905 AC XY: 123AN XY: 135890
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GnomAD4 exome AF: 0.000776 AC: 1134AN: 1461824Hom.: 4 Cov.: 32 AF XY: 0.000803 AC XY: 584AN XY: 727222
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GnomAD4 genome AF: 0.000900 AC: 137AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74438
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:5
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | ANO5: PM3:Strong, PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | Identified in individuals with limb-girdle muscular dystrophy and suspected limb-girdle muscular dystrophy who were heterozygous for this change and did not have another identifiable ANO5 pathogenic variant; however, additional clinical information was not provided and functional characterization of the variant was not completed (Savarese et al., 2015; Nallamilli et al., 2018); Reported previously in individuals with muscular dystrophy, suspected LGMD, and/or unspecified neuromuscular disorder with myopathic changes on biopsy who harborded another ANO5 pathogenic variant; however, segregation analysis was not provided and functional characterization of the variant was not performed (Penttila et al., 2012; Nallamilli et al., 2018; Gonzalez-Quereda et al., 2020).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23047743, 27884173, 30564623, 32403337, 22402862, 25891276) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 07, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 12, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 07, 2023 | The ANO5 c.2141C>G; p.Thr714Ser variant (rs200631556) is reported in the literature in multiple individuals affected with limb girdle muscular dystrophy and unspecified neuromuscular disorders; however, it is only rarely found with a second pathogenic ANO5 variant (Gonzalez-Quereda 2020, Nallamilli 2018, Savarese 2015). This variant is also reported in ClinVar (Variation ID: 195004) and is found in the general population with an overall allele frequency of 0.09% (250/282,842 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.498). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Gonzalez-Quereda L et al. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes (Basel). 2020 May 11;11(5):539. PMID: 32403337. Nallamilli BRR et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018 Dec 1;5(12):1574-1587. PMID: 30564623. Savarese M et al. Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations. Neuromuscul Disord. 2015 Jul;25(7):533-41. PMID: 25891276. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 08, 2023 | - - |
ANO5-Related Muscle Diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Gnathodiaphyseal dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 17, 2022 | - - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Uncertain
T
Polyphen
B
Vest4
MutPred
Gain of disorder (P = 0.0663);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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