rs886041222
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001368894.2(PAX6):c.823C>T(p.Arg275Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
PAX6
NM_001368894.2 stop_gained
NM_001368894.2 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.55
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-31793787-G-A is Pathogenic according to our data. Variant chr11-31793787-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 279862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX6 | NM_001368894.2 | c.823C>T | p.Arg275Ter | stop_gained | 11/14 | ENST00000640368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX6 | ENST00000640368.2 | c.823C>T | p.Arg275Ter | stop_gained | 11/14 | 5 | NM_001368894.2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aniridia 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 31, 2015 | - - |
Pathogenic, no assertion criteria provided | research | Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Wessex Regional Genetics Laboratory, Salisbury District Hospital | Aug 15, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 01, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. NMD-predicted variants resulting in loss of protein function have previously been reported in this gene (ClinVar). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 10 of 13). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have previously been reported pathogenic in clinical cases (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported pathogenic in individuals with aniridia (ClinVar). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
PAX6-related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) | Apr 27, 2023 | - - |
Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 07, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279862). This premature translational stop signal has been observed in individual(s) with aniridia (PMID: 10234503, 18483559, 22692063, 26661695, 28321846). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg261*) in the PAX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864). - |
Congenital ocular coloboma;C0155299:Coloboma of optic nerve;C0206115:11p partial monosomy syndrome;C0344542:Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis;C1833797:Isolated optic nerve hypoplasia;C1835698:Autosomal dominant keratitis;C3805604:Foveal hypoplasia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33120723, 31861090, 22692063, 18483559, 28321846, 29618921, 12634864, 26661695, 10234503, 25525159, 32360764) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at