chr11-22257711-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_213599.3(ANO5):c.1364G>A(p.Arg455His) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,612,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R455C) has been classified as Uncertain significance.
Frequency
Consequence
NM_213599.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANO5 | NM_213599.3 | c.1364G>A | p.Arg455His | missense_variant | 14/22 | ENST00000324559.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANO5 | ENST00000324559.9 | c.1364G>A | p.Arg455His | missense_variant | 14/22 | 1 | NM_213599.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000987 AC: 15AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251116Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135712
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1460290Hom.: 0 Cov.: 30 AF XY: 0.0000372 AC XY: 27AN XY: 726584
GnomAD4 genome AF: 0.0000987 AC: 15AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74252
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 13, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 04, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2024 | Variant summary: ANO5 c.1364G>A (p.Arg455His) results in a non-conservative amino acid change located in the anoctamin, transmembrane domain (IPR049452) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1364G>A in individuals affected with ANO5-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 285221). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2023 | The c.1364G>A (p.R455H) alteration is located in exon 14 (coding exon 14) of the ANO5 gene. This alteration results from a G to A substitution at nucleotide position 1364, causing the arginine (R) at amino acid position 455 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
ANO5-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 24, 2024 | The ANO5 c.1364G>A variant is predicted to result in the amino acid substitution p.Arg455His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-22279257-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANO5 protein function. ClinVar contains an entry for this variant (Variation ID: 285221). This variant has not been reported in the literature in individuals affected with ANO5-related conditions. This variant is present in population databases (rs772899863, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 455 of the ANO5 protein (p.Arg455His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at