rs757259413

Positions:

chr11-31794690-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001368894.2(PAX6):c.664C>T(p.Arg222Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAX6
NM_001368894.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.47

Variant links:

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]

PAX6 links:

PAX6 (HGNC:):

PAX6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAX6. . Gene score misZ 2.8175 (greater than the threshold 3.09). Trascript score misZ 3.256 (greater than threshold 3.09). GenCC has associacion of gene with Peters anomaly, coloboma, ocular, autosomal dominant, coloboma of optic nerve, aniridia 1, PAX6-related ocular dysgenesis, foveal hypoplasia 1, foveal hypoplasia-presenile cataract syndrome, isolated aniridia, diabetes mellitus, aniridia-cerebellar ataxia-intellectual disability syndrome, autosomal dominant keratitis, isolated optic nerve hypoplasia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 11-31794690-G-A is Pathogenic according to our data. Variant chr11-31794690-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-31794690-G-A is described in Lovd as [Pathogenic]. Variant chr11-31794690-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2 linkuse as main transcript	c.664C>T	p.Arg222Trp	missense_variant	9/14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2 linkuse as main transcript	c.664C>T	p.Arg222Trp	missense_variant	9/14	5	NM_001368894.2	ENSP00000492024.1		P26367-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251466

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aniridia 1

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Aug 15, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 21, 2020	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9147640, 12015275, 7550230, 8364574, 9482572, 10234503, 22361317, 10737978, 29450879, 32360764, 34415986, 29930474, 34344282, 35170016) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -

Irido-corneo-trabecular dysgenesis;C3805604:Foveal hypoplasia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 01, 2022

- -

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 17, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg208 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 10234503), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372441). This missense change has been observed in individuals with aniridia or congenital cataracts (PMID: 8364574, 22361317). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757259413, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 208 of the PAX6 protein (p.Arg208Trp). -

PAX6-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

The PAX6 c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant can also be designated c.622C>T (p.Arg208Trp) in transcript NM_001258464.1. This variant has been reported multiple times in individuals with PAX6-related disease, and in some cases was confirmed de novo (reported as c.622C>T p.Arg208Trp in Patel et al. 2018. PubMed ID: 29450879; Cross et al. 2020. PubMed ID: 32360764; Chesneau et al. 2022. PubMed ID: 35170016). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-31816238-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/372441/). Given all the evidence, we interpret c.664C>T (p.Arg222Trp) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;D;D;D;.;.;.;.;.;D;D;D;D;D;D;.;D;D;.;D;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

.;.;.;M;M;M;M;M;.;M;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.0

.;.;D;.;.;.;D;D;D;.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

.;.;D;.;.;.;D;D;D;.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;.;.;D;.;D;.;.;.;D;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0

.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.84

MutPred

0.84

.;.;.;Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);.;Loss of solvent accessibility (P = 0.001);.;.;.;.;.;.;Loss of solvent accessibility (P = 0.001);.;Loss of solvent accessibility (P = 0.001);.;.;.;.;.;.;.;Loss of solvent accessibility (P = 0.001);.;.;.;.;.;Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);.;.;Loss of solvent accessibility (P = 0.001);.;.;.;Loss of solvent accessibility (P = 0.001);.;.;.;.;.;.;.;.;.;.;Loss of solvent accessibility (P = 0.001);.;.;.;.;

MVP

0.94

MPC

2.1

ClinPred

1.0

GERP RS

5.6

Varity_R

0.80

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over