chr11-22259733-C-CA
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_213599.3(ANO5):c.1627dupA(p.Met543AsnfsTer11) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_213599.3 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250076Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135190
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1458940Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 725948
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
Miyoshi muscular dystrophy 3 Pathogenic:2
The homozygous p.Met543AsnfsTer11 variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy. The p.Met543AsnfsTer11 variant in ANO5 has been previously reported in 8 unrelated individuals with ANO5-related muscle disease (PMID: 34008892, PMID: 30919934, PMID: 25891276, PMID: 23606453, PMID: 22742934, PMID: 22402862, PMID: 22194990) and segregated with disease in 4 affected relatives from 2 families, but has been identified in 0.01% (4/35334) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1412514693). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 8 affected individuals, 3 were homozygotes (PMID: 30919934, PMID: 25891276, PMID: 22742934) and 4 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 22194990, PMID: 23606453, ClinVar Variation ID: 2164; PMID: 34008892, ClinVar Variation ID: 2166), which increases the likelihood that the p.Met543AsnfsTer11 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 285942) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 543 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ANO5 gene is an established disease mechanism in autosomal recessive ANO5-related muscle disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ANO5-related muscle disease. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1 (Richards 2015). -
PVS1, PM2, PP3 -
Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:2
The homozgous c.1627dupA variant was identified by our study in one individual with Limb-Girdle Muscular Dystrophy. The c.1627dupA variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -
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not provided Pathogenic:1
The c.1627dupA ANO5 pathogenic variant has been reported in individuals with LGMD2L1 and is of a type expected to cause disease. 1. www.lovd.nl/ANO5 AKT 9-7-16 -
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1
This sequence change creates a premature translational stop signal (p.Met543Asnfs*11) in the ANO5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs768746440, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ANO5-related myopathies and/or limb girdle muscular dystrophy 2L (PMID: 22194990, 22402862, 22742934, 23606453, 25891276). ClinVar contains an entry for this variant (Variation ID: 285942). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at