11-31802733-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001368894.2(PAX6):c.112C>G(p.Arg38Gly) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

PAX6
NM_001368894.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.38

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 Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-31802732-C-G is described in Lovd as [Likely_pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 11-31802733-G-C is Pathogenic according to our data. Variant chr11-31802733-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-31802733-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2 link	c.112C>G	p.Arg38Gly	missense_variant	Exon 5 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.112C>G	p.Arg38Gly	missense_variant	Exon 5 of 14	5	NM_001368894.2	ENSP00000492024.1		P26367-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aniridia 1

Pathogenic:1

Jul 04, 2018

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PP3, PP4 -

Foveal hypoplasia 1

Pathogenic:1

Aug 15, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

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

0.95

MetaRNN

Pathogenic

0.98

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

1.0

MutationAssessor

Pathogenic

3.8

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

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.9

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

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

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

0.93

MutPred

0.90

Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);.;Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);

MVP

1.0

MPC

4.0

ClinPred

0.99

GERP RS

3.6

Varity_R

0.94

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over