rs137854528
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PP5_ModerateBS2_Supporting
The NM_213599.3(ANO5):βc.2311_2312delβ(p.Gln771AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000046 ( 0 hom., cov: 32)
Exomes π: 0.000021 ( 0 hom. )
Consequence
ANO5
NM_213599.3 frameshift
NM_213599.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.108
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_pathogenic. Variant got 9 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-22274639-CCA-C is Pathogenic according to our data. Variant chr11-22274639-CCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 39277.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-22274639-CCA-C is described in Lovd as [Pathogenic].
BS2
High AC in GnomAd4 at 7 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 | UniProt |
---|---|---|---|---|---|---|---|
ANO5 | NM_213599.3 | c.2311_2312del | p.Gln771AlafsTer8 | frameshift_variant | 20/22 | ENST00000324559.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANO5 | ENST00000324559.9 | c.2311_2312del | p.Gln771AlafsTer8 | frameshift_variant | 20/22 | 1 | NM_213599.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151874Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251176Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135754
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461336Hom.: 0 AF XY: 0.0000220 AC XY: 16AN XY: 726972
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GnomAD4 genome AF: 0.0000461 AC: 7AN: 151874Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6AN XY: 74170
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 20, 2012 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39277). This premature translational stop signal has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 22402862). This variant is present in population databases (rs746988059, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Gln771Alafs*8) 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). - |
not provided Other:1
not provided, no classification provided | literature only | ANO5 @LOVD | - | - - |
Computational scores
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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