11-31791034-C-T

Position:

• chr11-31791034-C-T

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.1075-174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 762,266 control chromosomes in the GnomAD database, including 215,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37626 hom., cov: 32)
  • Exomes 𝑓: 0.76 (177969 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.655

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-31791034-C-T is Benign according to our data. Variant chr11-31791034-C-T is described in ClinVar as [Benign]. Clinvar id is 674009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.1075-174G>A		intron_variant		ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.1075-174G>A		intron_variant		5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104691 AN: 151948 Hom.: 37613 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.870

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.712

GnomAD4 exome AF: 0.757 AC: 461623 AN: 610200 Hom.: 177969 Cov.: 7 AF XY: 0.762 AC XY: 248946 AN XY: 326622

Gnomad4 AFR exome AF: 0.511

Gnomad4 AMR exome AF: 0.557

Gnomad4 ASJ exome AF: 0.777

Gnomad4 EAS exome AF: 0.492

Gnomad4 SAS exome AF: 0.759

Gnomad4 FIN exome AF: 0.769

Gnomad4 NFE exome AF: 0.808

Gnomad4 OTH exome AF: 0.734

GnomAD4 genome AF: 0.689 AC: 104736 AN: 152066 Hom.: 37626 Cov.: 32 AF XY: 0.687 AC XY: 51052 AN XY: 74344

Gnomad4 AFR AF: 0.498

Gnomad4 AMR AF: 0.642

Gnomad4 ASJ AF: 0.786

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.772

Gnomad4 NFE AF: 0.805

Gnomad4 OTH AF: 0.715

Alfa AF: 0.777 Hom.: 63791

Bravo AF: 0.667

Asia WGS AF: 0.605 AC: 2106 AN: 3478

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.3
DANN	Benign	0.83

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: rs2071754; hg19: chr11-31812582;