rs1554985722

Positions:

• chr11-31802714-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_001368894.2(PAX6):​c.131G>C​(p.Arg44Pro) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAX6 NM_001368894.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAX6. . Gene score misZ 2.8175 (greater than the threshold 3.09). Trascript score misZ 3.256 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.987
• PP5: Variant 11-31802714-C-G is Pathogenic according to our data. Variant chr11-31802714-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 430901.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.131G>C	p.Arg44Pro	missense_variant	5/14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.131G>C	p.Arg44Pro	missense_variant	5/14	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental cataract;C0026010:Microphthalmia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Fundació de Recerca de l'Institut de Microcirurgia Ocular

Apr 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
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	0.92	D
MetaRNN	Pathogenic	0.99	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	0.96	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	.;.;D;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;.;.;.;D;.;D;.;D;.;D;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;.;.;.;D;.;D;.;D;.;D;.;.;.;.;.;.;T;.
Sift4G	Pathogenic	0.0	D;.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
Polyphen		1.0	.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.97
MutPred		0.89		Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);.;Loss of MoRF binding (P = 0.0213);Loss of MoRF binding (P = 0.0213);
MVP		0.99
MPC		4.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.98

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: rs1554985722; hg19: chr11-31824262;