11-31801560-C-T

Variant names:

• chr11-31801560-C-T
• rs398123295
• NM_001368894.2:c.399+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001368894.2(PAX6):​c.399+1G>A variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX6 NM_001368894.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.87
• Publications: 9 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.16475973 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-31801560-C-T is Pathogenic according to our data. Variant chr11-31801560-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 92758.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	c.399+1G>A		splice_donor_variant, intron_variant	Intron 7 of 13	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.399+1G>A		splice_donor_variant, intron_variant	Intron 7 of 13	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000534 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Sep 04, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16712695, 19218613, 26661695, 25525159, 10234503, 23761016, 12552561, 32360764, 34101622, 34942114, 38002984, 38459225, 39212610, 38219857, 33782094, 8364574, 9138149, 36729443) -

Feb 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aniridia 1 Pathogenic:3

Sep 18, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000092758 /PMID: 8364574). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 10, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP3, PP5 -

Aug 15, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 92758). Disruption of this splice site has been observed in individual(s) with aniridia (PMID: 8364574, 26661695). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 6 of the PAX6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864). -

PAX6-related disorder Pathogenic:1

Nov 16, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PAX6 c.399+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as causative for aniridia and in some cases was found to arise de novo (Figure 3b in Hanson et al. 1993. PubMed ID: 8364574; reported as c.357+1G>A in Cross et al. 2020. PubMed ID: 32360764; Table S1 in Kit et al. 2021. PubMed ID: 34101622). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in PAX6 are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/92758). Given all the evidence, we interpret c.399+1G>A as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		7.9
GERP RS		4.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.52		Position offset: 28
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs398123295; hg19: chr11-31823108; COSMIC: COSV53792430; COSMIC: COSV53792430;