11-31800703-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001368894.2(PAX6):c.553C>A(p.Gln185Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAX6
NM_001368894.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.31

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2 link	c.553C>A	p.Gln185Lys	missense_variant	Exon 8 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.553C>A	p.Gln185Lys	missense_variant	Exon 8 of 14	5	NM_001368894.2	ENSP00000492024.1		P26367-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis

Uncertain:1

Jan 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 171 of the PAX6 protein (p.Gln171Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAX6-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAX6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Uncertain

0.53

.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.

Eigen

Benign

-0.094

Eigen_PC

Benign

0.087

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;T;T;T;T;T;T;.;T;T;.;T;.;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.0

.;.;.;L;L;L;L;L;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.0

.;.;N;.;.;.;N;N;N;.;.;N;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.50

Sift

Benign

0.54

.;.;T;.;.;.;T;T;T;.;.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.94

T;.;T;.;.;.;T;.;T;.;.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.0

.;.;.;B;B;B;B;B;.;B;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.67

MutPred

0.42

.;.;.;Gain of ubiquitination at Q171 (P = 0.0037);Gain of ubiquitination at Q171 (P = 0.0037);Gain of ubiquitination at Q171 (P = 0.0037);Gain of ubiquitination at Q171 (P = 0.0037);Gain of ubiquitination at Q171 (P = 0.0037);.;Gain of ubiquitination at Q171 (P = 0.0037);.;.;.;.;.;Gain of ubiquitination at Q171 (P = 0.0037);Gain of ubiquitination at Q171 (P = 0.0037);.;.;.;.;.;.;.;Gain of ubiquitination at Q171 (P = 0.0037);.;.;.;.;.;Gain of ubiquitination at Q171 (P = 0.0037);Gain of ubiquitination at Q171 (P = 0.0037);.;.;Gain of ubiquitination at Q171 (P = 0.0037);.;.;.;Gain of ubiquitination at Q171 (P = 0.0037);.;.;.;.;.;.;.;.;.;Gain of ubiquitination at Q171 (P = 0.0037);.;.;.;.;

MVP

0.99

MPC

1.1

ClinPred

0.54

GERP RS

4.3

Varity_R

0.42

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over