rs200633920
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_213599.3(ANO5):c.1363C>T(p.Arg455Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R455H) has been classified as Uncertain significance.
Frequency
Consequence
NM_213599.3 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- gnathodiaphyseal dysplasiaInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
- autosomal recessive limb-girdle muscular dystrophy type 2LInheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
- Miyoshi muscular dystrophy 3Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152052Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251174 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1460286Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 726558 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152052Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74274 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.1363C>T (p.R455C) alteration is located in exon 14 (coding exon 14) of the ANO5 gene. This alteration results from a C to T substitution at nucleotide position 1363, causing the arginine (R) at amino acid position 455 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
ClinVar contains an entry for this variant (Variation ID: 578034). 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 expected to disrupt ANO5 protein function. This variant has not been reported in the literature in individuals affected with ANO5-related conditions. This variant is present in population databases (rs200633920, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 455 of the ANO5 protein (p.Arg455Cys). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at