11-31797626-A-G

Variant names:

• chr11-31797626-A-G
• rs628224
• NM_001368894.2:c.566-2838T>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.566-2838T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.878 in 152,098 control chromosomes in the GnomAD database, including 58,969 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 0.88 (58969 hom., cov: 30)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 14 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.96 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.566-2838T>C		intron	N/A	NP_001355823.1
	PAX6	NM_001368910.2		c.767-2838T>C		intron	N/A	NP_001355839.1
	PAX6	NM_001368911.2		c.569-2838T>C		intron	N/A	NP_001355840.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000640368.2	TSL:5 MANE Select	c.566-2838T>C		intron	N/A	ENSP00000492024.1
	PAX6	ENST00000419022.6	TSL:1	c.566-2838T>C		intron	N/A	ENSP00000404100.1
	PAX6	ENST00000638914.3	TSL:1	c.566-2838T>C		intron	N/A	ENSP00000492315.2

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133438 AN: 151980 Hom.: 58913 Cov.: 30

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.825

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.884

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.878 AC: 133555 AN: 152098 Hom.: 58969 Cov.: 30 AF XY: 0.876 AC XY: 65093 AN XY: 74344

African (AFR) AF: 0.968 AC: 40186 AN: 41504

American (AMR) AF: 0.824 AC: 12594 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3082 AN: 3468

East Asian (EAS) AF: 0.700 AC: 3602 AN: 5148

South Asian (SAS) AF: 0.822 AC: 3948 AN: 4802

European-Finnish (FIN) AF: 0.847 AC: 8976 AN: 10592

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

European-Non Finnish (NFE) AF: 0.857 AC: 58243 AN: 67988

Other (OTH) AF: 0.885 AC: 1869 AN: 2112

Alfa AF: 0.858 Hom.: 13400

Bravo AF: 0.879

Asia WGS AF: 0.794 AC: 2765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.80
DANN	Benign	0.14
PhyloP100		-1.2
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: rs628224; hg19: chr11-31819174;