rs644242

chr11-31791253-C-Achr11-31791253-C-G

Variant summary

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

The NM_001368894.2(PAX6):c.1075-393G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 355,048 control chromosomes in the GnomAD database, including 1,073 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 0.061 (397 hom., cov: 32)
  • Exomes 𝑓: 0.069 (676 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730

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=-0.61).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX6	NM_001368894.2	c.1075-393G>T		intron_variant		ENST00000640368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.1075-393G>T		intron_variant		5	NM_001368894.2

Frequencies

GnomAD3 genomes AF: 0.0613 AC: 9324 AN: 152074 Hom.: 397 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0690

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0727

GnomAD4 exome AF: 0.0686 AC: 13923 AN: 202856 Hom.: 676 Cov.: 0 AF XY: 0.0681 AC XY: 7456 AN XY: 109432

Gnomad4 AFR exome AF: 0.0417

Gnomad4 AMR exome AF: 0.170

Gnomad4 ASJ exome AF: 0.0781

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.0726

Gnomad4 FIN exome AF: 0.0528

Gnomad4 NFE exome AF: 0.0497

Gnomad4 OTH exome AF: 0.0743

GnomAD4 genome AF: 0.0612 AC: 9319 AN: 152192 Hom.: 397 Cov.: 32 AF XY: 0.0636 AC XY: 4730 AN XY: 74398

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.0717

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.0682

Gnomad4 FIN AF: 0.0498

Gnomad4 NFE AF: 0.0493

Gnomad4 OTH AF: 0.0719

Alfa AF: 0.0437 Hom.: 107

Bravo AF: 0.0701

Asia WGS AF: 0.139 AC: 481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	4.6
Dann	Benign	0.78

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: rs644242; hg19: chr11-31812801;