rs1131692293

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001368894.2(PAX6):c.193G>A(p.Gly65Arg) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G65V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PAX6
NM_001368894.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.87

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

aniridia 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
PAX6-related ocular dysgenesis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Peters anomaly
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
coloboma, ocular, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
foveal hypoplasia-presenile cataract syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated aniridia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated optic nerve hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant keratitis
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

PAX6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 23 ACMG points.

PS1

Transcript NM_001368894.2 (PAX6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001368894.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-31801766-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68469.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the PAX6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 75 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.8175 (below the threshold of 3.09). Trascript score misZ: 3.256 (above the threshold of 3.09). GenCC associations: The gene is linked to Peters anomaly, diabetes mellitus, aniridia-cerebellar ataxia-intellectual disability syndrome, foveal hypoplasia-presenile cataract syndrome, aniridia 1, PAX6-related ocular dysgenesis, coloboma, ocular, autosomal dominant, isolated optic nerve hypoplasia, autosomal dominant keratitis, isolated aniridia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 11-31801767-C-T is Pathogenic according to our data. Variant chr11-31801767-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 430982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2 link	c.193G>A	p.Gly65Arg	missense_variant	Exon 7 of 14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2 link	c.193G>A	p.Gly65Arg	missense_variant	Exon 7 of 14	5	NM_001368894.2	ENSP00000492024.1		P26367-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aniridia 1

Pathogenic:2

Aug 15, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:2

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 31700164, 28321846, 32360764, 33057194, 35982159, 38219857, 16712695, 36980880) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.95

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

M_CAP

Pathogenic

0.89

MetaRNN

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;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.8

.;.;.;H;H;H;H;H;.;H;.;.;.;.;.;.;H;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.8

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

REVEL

Pathogenic

1.0

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96

MutPred

0.97

.;.;.;Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);.;Gain of MoRF binding (P = 0.0059);.;.;.;.;.;Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);.;Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);.;.;.;Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);.;.;.;.;Gain of MoRF binding (P = 0.0059);.;.;.;.;

MVP

1.0

MPC

2.2

ClinPred

1.0

GERP RS

5.3

Varity_R

0.96

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over