rs2239789

Variant names:

• chr11-31794348-T-A
• rs2239789
• NM_001368894.2:c.725-234A>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• aniridia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• PAX6-related ocular dysgenesis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Peters anomaly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• coloboma, ocular, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• foveal hypoplasia-presenile cataract syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated aniridia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated optic nerve hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant keratitis

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.725-234A>T		intron_variant	Intron 9 of 13	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.725-234A>T		intron_variant	Intron 9 of 13	5	NM_001368894.2	ENSP00000492024.1

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

African (AFR) AF: 0.325 AC: 4150 AN: 12768

American (AMR) AF: 0.369 AC: 7452 AN: 20204

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 6578 AN: 13996

East Asian (EAS) AF: 0.463 AC: 14290 AN: 30876

South Asian (SAS) AF: 0.596 AC: 27674 AN: 46424

European-Finnish (FIN) AF: 0.468 AC: 13579 AN: 29028

Middle Eastern (MID) AF: 0.490 AC: 1683 AN: 3432

European-Non Finnish (NFE) AF: 0.519 AC: 144585 AN: 278324

Other (OTH) AF: 0.478 AC: 12671 AN: 26520

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

African (AFR) AF: 0.325 AC: 13370 AN: 41118

American (AMR) AF: 0.414 AC: 6301 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1675 AN: 3470

East Asian (EAS) AF: 0.457 AC: 2334 AN: 5110

South Asian (SAS) AF: 0.591 AC: 2817 AN: 4770

European-Finnish (FIN) AF: 0.469 AC: 4884 AN: 10420

Middle Eastern (MID) AF: 0.407 AC: 118 AN: 290

European-Non Finnish (NFE) AF: 0.519 AC: 35207 AN: 67814

Other (OTH) AF: 0.488 AC: 1025 AN: 2102

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.9
DANN	Benign	0.76
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2239789; hg19: chr11-31815896;