rs1131692282

chr11-31806926-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_001368894.2(PAX6):c.-128-2del variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX6 NM_001368894.2 splice_acceptor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.18

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.8, offset of -35, new splice context is: cgtatgctgttgaaccacAGctt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-31806926-CT-C is Pathogenic according to our data. Variant chr11-31806926-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 430969.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.-128-2del		splice_acceptor_variant		ENST00000640368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.-128-2del		splice_acceptor_variant		5	NM_001368894.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aniridia 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Aug 15, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 30291432). ClinVar contains an entry for this variant (Variation ID: 430969). This variant is also known as IVS2-2delA. This variant has been observed in individual(s) with aniridia (PMID: 9281415, 28321846, 30291432, 32360764). In at least one individual the variant was observed to be de novo. 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 falls in intron 2 of the PAX6 gene. It does not directly change the encoded amino acid sequence of the PAX6 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.65		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131692282; hg19: chr11-31828474;