rs2239789

Positions:

• chr11-31794348-T-A
• chr11-31794348-T-C
• chr11-31794348-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001368894.2(PAX6):​c.725-234A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 612,804 control chromosomes in the GnomAD database, including 76,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15966 hom., cov: 29)
  • Exomes 𝑓: 0.50 (60199 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.392

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-31794348-T-A is Benign according to our data. Variant chr11-31794348-T-A is described in ClinVar as [Benign]. Clinvar id is 1271937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.725-234A>T		intron_variant		ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.725-234A>T		intron_variant		5	NM_001368894.2	ENSP00000492024

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68120 AN: 151112 Hom.: 15949 Cov.: 29

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.426

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.480

GnomAD4 exome AF: 0.504 AC: 232662 AN: 461572 Hom.: 60199 Cov.: 3 AF XY: 0.512 AC XY: 125770 AN XY: 245758

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.369

Gnomad4 ASJ exome AF: 0.470

Gnomad4 EAS exome AF: 0.463

Gnomad4 SAS exome AF: 0.596

Gnomad4 FIN exome AF: 0.468

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.451 AC: 68158 AN: 151232 Hom.: 15966 Cov.: 29 AF XY: 0.451 AC XY: 33270 AN XY: 73812

Gnomad4 AFR AF: 0.325

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.483

Gnomad4 EAS AF: 0.457

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.488

Alfa AF: 0.484 Hom.: 2226

Bravo AF: 0.437

Asia WGS AF: 0.502 AC: 1720 AN: 3422

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.9
DANN	Benign	0.76

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: rs2239789; hg19: chr11-31815896;