rs1806158

Positions:

• chr11-31817240-C-G
• chr11-31817240-C-T

Variant summary

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

The ENST00000638914.3(PAX6):​c.-317+569G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,290 control chromosomes in the GnomAD database, including 4,158 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 0.22 (4158 hom., cov: 35)
• Consequence: PAX6 ENST00000638914.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.761

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]

PAUPAR (HGNC:49670): (PAX6 upstream antisense RNA) This gene is thought to produce a functional long non-coding RNA. Knockdown of this transcript results in genome-wide changes in gene expression, particularly of cell cyle genes, indicating a role in regulating differentiation. This transcript may bind to the promoter region of target genes and may also interact with the transcription factor Pax6 (paired box 6). [provided by RefSeq, Feb 2015]

PAX6-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6-AS1	NR_033971.1	n.74+601C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAUPAR	ENST00000644607.1	n.374+601C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33812 AN: 152172 Hom.: 4152 Cov.: 35

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.222 AC: 33854 AN: 152290 Hom.: 4158 Cov.: 35 AF XY: 0.221 AC XY: 16466 AN XY: 74472

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.186

Alfa AF: 0.104 Hom.: 158

Bravo AF: 0.228

Asia WGS AF: 0.225 AC: 782 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.74
DANN	Benign	0.57

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

LitVar

Other links and lift over

dbSNP: rs1806158; hg19: chr11-31838788;