11-31797626-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001368894.2(PAX6):c.566-2838T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.878 in 152,098 control chromosomes in the GnomAD database, including 58,969 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.88 (58969 hom., cov: 30)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX6	NM_001368894.2	c.566-2838T>C		intron_variant		ENST00000640368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.566-2838T>C		intron_variant		5	NM_001368894.2

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133438 AN: 151980 Hom.: 58913 Cov.: 30

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.825

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.884

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.878 AC: 133555 AN: 152098 Hom.: 58969 Cov.: 30 AF XY: 0.876 AC XY: 65093 AN XY: 74344

Gnomad4 AFR AF: 0.968

Gnomad4 AMR AF: 0.824

Gnomad4 ASJ AF: 0.889

Gnomad4 EAS AF: 0.700

Gnomad4 SAS AF: 0.822

Gnomad4 FIN AF: 0.847

Gnomad4 NFE AF: 0.857

Gnomad4 OTH AF: 0.885

Alfa AF: 0.862 Hom.: 4217

Bravo AF: 0.879

Asia WGS AF: 0.794 AC: 2765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.80
Dann	Benign	0.14

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: rs628224; hg19: chr11-31819174;