rs121907918
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001368894.2(PAX6):c.424C>T(p.Arg142Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001368894.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX6 | NM_001368894.2 | c.424C>T | p.Arg142Cys | missense_variant | 8/14 | ENST00000640368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX6 | ENST00000640368.2 | c.424C>T | p.Arg142Cys | missense_variant | 8/14 | 5 | NM_001368894.2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Aniridia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Wessex Regional Genetics Laboratory, Salisbury District Hospital | Aug 15, 2019 | - - |
Foveal hypoplasia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 28, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg128 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18332330). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PAX6 function (PMID: 14744876, 23404109, 27013732). 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) performed at Invitae indicates that this missense variant is expected to disrupt PAX6 protein function. ClinVar contains an entry for this variant (Variation ID: 3470). This variant is also known as R125C. This missense change has been observed in individual(s) with foveal hypoplasia (PMID: 8640214, 32360764). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 128 of the PAX6 protein (p.Arg128Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at