11-31803970-T-G

Variant names:

• chr11-31803970-T-G
• rs694617
• NM_001368894.2:c.11-1136A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001368894.2(PAX6):​c.11-1136A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.87 in 152,226 control chromosomes in the GnomAD database, including 57,874 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 0.87 (57827 hom., cov: 30)
  • Exomes 𝑓: 0.91 (47 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368894.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	NM_001368894.2	MANE Select	c.11-1136A>C		intron	N/A	NP_001355823.1
	PAX6	NM_001310160.2		c.-1907A>C		5_prime_UTR	Exon 1 of 10	NP_001297089.1
	PAX6	NM_001310161.3		c.-459A>C		5_prime_UTR	Exon 1 of 11	NP_001297090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000640368.2	TSL:5 MANE Select	c.11-1136A>C		intron	N/A	ENSP00000492024.1
	PAX6	ENST00000419022.6	TSL:1	c.11-1136A>C		intron	N/A	ENSP00000404100.1
	PAX6	ENST00000638914.3	TSL:1	c.11-1136A>C		intron	N/A	ENSP00000492315.2

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132263 AN: 151992 Hom.: 57777 Cov.: 30

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.822

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.824

Gnomad FIN AF: 0.848

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.877

GnomAD4 exome AF: 0.905 AC: 105 AN: 116 Hom.: 47 Cov.: 0 AF XY: 0.927 AC XY: 76 AN XY: 82

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 4 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.889 AC: 16 AN: 18

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.907 AC: 78 AN: 86

Other (OTH) AF: 0.875 AC: 7 AN: 8

GnomAD4 genome AF: 0.870 AC: 132374 AN: 152110 Hom.: 57827 Cov.: 30 AF XY: 0.868 AC XY: 64538 AN XY: 74330

African (AFR) AF: 0.938 AC: 38940 AN: 41494

American (AMR) AF: 0.822 AC: 12561 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 3084 AN: 3472

East Asian (EAS) AF: 0.703 AC: 3614 AN: 5144

South Asian (SAS) AF: 0.823 AC: 3969 AN: 4820

European-Finnish (FIN) AF: 0.848 AC: 8961 AN: 10572

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.858 AC: 58331 AN: 68000

Other (OTH) AF: 0.878 AC: 1857 AN: 2114

Alfa AF: 0.846 Hom.: 2853

Bravo AF: 0.870

Asia WGS AF: 0.794 AC: 2766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		1.1
PromoterAI		-0.061	Neutral
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: rs694617; hg19: chr11-31825518;