rs121907916

Variant names:

• chr11-31794705-G-A
• rs121907916
• NM_001368894.2:c.649C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-31794705-G-A
• chr11-31794705-G-C
• chr11-31794705-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001368894.2(PAX6):​c.649C>T​(p.Arg217*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX6 NM_001368894.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.43

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-31794705-G-A is Pathogenic according to our data. Variant chr11-31794705-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3466.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.649C>T	p.Arg217*	stop_gained	Exon 9 of 14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.649C>T	p.Arg217*	stop_gained	Exon 9 of 14	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aniridia 1 Pathogenic:4

Feb 07, 2018

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:2

Feb 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay 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: 27463523, 24390526, 22171686, 25525159, 7550230, 12552561, 29618921, 29901133, 28321846, 32360764, 10887930, 34101622, 27535533) -

Jul 29, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.607C>T (p.R203*) alteration, located in exon 8 (coding exon 5) of the PAX6 gene, consists of a C to T substitution at nucleotide position 607. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 203. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was identified in multiple individuals with features consistent with PAX6-related ophthalmological disorder and segregated with disease in at least one family (Cross, 2020; Daruich, 2022; Dubey, 2015; Kuchalska, 2023; Moon, 2021; Souzeau, 2018; Syrimis, 2018; Zucco, 2024). This variant has been determined to be the result of a de novo mutation in at least one individual with features consistent with PAX6-related ophthalmological disorder (Cross, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

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

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg203*) in the PAX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with aniridia, and microphthalmia with late-onset keratitis and iris coloboma and aniridia with slightly impaired pituitary function (PMID: 10887930, 22171686, 24390526, 27463523). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PAX6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 10,718 individuals referred to our laboratory for PAX6 testing. This variant is also known as c.649C>T; p.Arg217_x0001_*. ClinVar contains an entry for this variant (Variation ID: 3466). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.89
GERP RS		4.8

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

Other links and lift over

dbSNP: rs121907916; hg19: chr11-31816253; COSMIC: COSV53792293; COSMIC: COSV53792293;