rs1131692286
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001368894.2(PAX6):c.78del(p.Gln27ArgfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
PAX6
NM_001368894.2 frameshift
NM_001368894.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.429
Genes affected
PAX6 (HGNC:8620): (paired box 6) This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 255 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-31802766-GC-G is Pathogenic according to our data. Variant chr11-31802766-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 430974.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX6 | NM_001368894.2 | c.78del | p.Gln27ArgfsTer4 | frameshift_variant | 5/14 | ENST00000640368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX6 | ENST00000640368.2 | c.78del | p.Gln27ArgfsTer4 | frameshift_variant | 5/14 | 5 | NM_001368894.2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Aniridia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics | - | - - |
Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864). A different variant (c.80delA) giving rise to the same protein effect observed here (p.Gln27Argfs*4) has been determined to be pathogenic (PMID: 10737978). This suggests that this variant is also likely to be causative of disease. This variant has been observed to be de novo in an individual affected with aniridia (PMID: 28321846). ClinVar contains an entry for this variant (Variation ID: 430974). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln27Argfs*4) in the PAX6 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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Calibrated prediction
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Splicing
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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