rs137854524
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The NM_213599.3(ANO5):āc.1295C>Gā(p.Ala432Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,304 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 Pathogenic (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000010 ( 0 hom. )
Consequence
ANO5
NM_213599.3 missense
NM_213599.3 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 2.50
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 Pathogenic. Variant got 10 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 11-22255485-C-G is Pathogenic according to our data. Variant chr11-22255485-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22255485-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANO5 | NM_213599.3 | c.1295C>G | p.Ala432Gly | missense_variant | 13/22 | ENST00000324559.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANO5 | ENST00000324559.9 | c.1295C>G | p.Ala432Gly | missense_variant | 13/22 | 1 | NM_213599.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152026Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250624Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135462
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461278Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 726964
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74222
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 19, 2015 | - - |
not provided, no classification provided | literature only | ANO5 @LOVD | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 26, 2019 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 12, 2010 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2023 | Variant summary: ANO5 c.1295C>G (p.Ala432Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. Muscle cDNA from a homozygous patient confirmed aberrant splicing of exon 13 that resulted in the deletion of the last 38 nucleotides of this exon leading to a frameshift and a predicted premature truncation (p.Ala432GlyfsX49) (Bolduc_2010). The variant allele was found at a frequency of 2.8e-05 in 250624 control chromosomes (gnomAD). c.1295C>G has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Bolduc_2010, Levesque_2016, Silva_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20096397, 26809617, 31353849). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L;C2750076:Miyoshi muscular dystrophy 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 18, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 20096397). The resulting mRNA is expected to undergo nonsense-mediated decay. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO5 protein function. ClinVar contains an entry for this variant (Variation ID: 2163). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 20096397, 26809617, 31353849). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs137854524, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 432 of the ANO5 protein (p.Ala432Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
A
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
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DS_DL_spliceai
Position offset: 37
Find out detailed SpliceAI scores and Pangolin per-transcript scores at