rs667773

Variant names:

• chr11-31793814-G-A
• rs667773
• NM_001368894.2:c.808-12C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001368894.2(PAX6):​c.808-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0583 in 1,613,838 control chromosomes in the GnomAD database, including 3,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.062 (401 hom., cov: 32)
  • Exomes 𝑓: 0.058 (3446 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Scores: Splicing: ADA: 0.00001295
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: -0.149
• Publications: 23 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: G2P, Genomics England PanelApp, 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• diabetes mellitus

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

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

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-31793814-G-A is Benign according to our data. Variant chr11-31793814-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258168.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	NM_001368894.2	MANE Select	c.808-12C>T		intron	N/A	NP_001355823.1	P26367-2
	PAX6	NM_001368910.2		c.1009-12C>T		intron	N/A	NP_001355839.1
	PAX6	NM_001368911.2		c.811-12C>T		intron	N/A	NP_001355840.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000640368.2	TSL:5 MANE Select	c.808-12C>T		intron	N/A	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.808-12C>T		intron	N/A	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.808-12C>T		intron	N/A	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.0617 AC: 9378 AN: 152074 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0718

GnomAD2 exomes AF: 0.0851 AC: 21382 AN: 251158 AF XY: 0.0795

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.0813

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.0496

Gnomad NFE exome AF: 0.0501

Gnomad OTH exome AF: 0.0822

GnomAD4 exome AF: 0.0579 AC: 84652 AN: 1461646 Hom.: 3446 Cov.: 33 AF XY: 0.0576 AC XY: 41876 AN XY: 727132

African (AFR) AF: 0.0436 AC: 1459 AN: 33476

American (AMR) AF: 0.193 AC: 8625 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0745 AC: 1947 AN: 26132

East Asian (EAS) AF: 0.148 AC: 5893 AN: 39694

South Asian (SAS) AF: 0.0697 AC: 6008 AN: 86254

European-Finnish (FIN) AF: 0.0520 AC: 2776 AN: 53406

Middle Eastern (MID) AF: 0.124 AC: 718 AN: 5768

European-Non Finnish (NFE) AF: 0.0476 AC: 52947 AN: 1111816

Other (OTH) AF: 0.0709 AC: 4279 AN: 60384

GnomAD4 genome AF: 0.0616 AC: 9373 AN: 152192 Hom.: 401 Cov.: 32 AF XY: 0.0639 AC XY: 4756 AN XY: 74408

African (AFR) AF: 0.0418 AC: 1736 AN: 41514

American (AMR) AF: 0.130 AC: 1988 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3470

East Asian (EAS) AF: 0.193 AC: 996 AN: 5164

South Asian (SAS) AF: 0.0681 AC: 328 AN: 4814

European-Finnish (FIN) AF: 0.0499 AC: 529 AN: 10610

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3348 AN: 68010

Other (OTH) AF: 0.0710 AC: 150 AN: 2112

Alfa AF: 0.0558 Hom.: 89

Bravo AF: 0.0704

Asia WGS AF: 0.139 AC: 481 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	11p partial monosomy syndrome (1)
-	1	-	Abnormality of refraction (1)
-	-	1	Aniridia 1 (1)
-	-	1	Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis (1)
-	-	1	Aniridia, Cerebellar Ataxia, And Intellectual Disability (1)
-	-	1	Anophthalmia-microphthalmia syndrome (1)
-	-	1	Autosomal dominant keratitis (1)
-	-	1	carboxymethyl-dextran-A2-gadolinium-DOTA (1)
-	-	1	Foveal hypoplasia 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.7
DANN	Benign	0.50
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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: rs667773; hg19: chr11-31815362; COSMIC: COSV53795119; COSMIC: COSV53795119;