rs667773

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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:1B:16

Conservation

PhyloP100: -0.149

Publications

23 publications found

Variant links:

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

PAX6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2 link	c.808-12C>T		intron_variant	Intron 10 of 13	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2 link	c.808-12C>T		intron_variant	Intron 10 of 13	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes

AF:

0.0617

AC:

9378

AN:

152074

Hom.:

401

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0576

AC XY:

41876

AN XY:

727132

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4721

9442

14162

18883

23604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2182

4364

6546

8728

10910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0616

AC:

9373

AN:

152192

Hom.:

401

Cov.:

AF XY:

0.0639

AC XY:

4756

AN XY:

74408

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0492

AC:

3348

AN:

68010

Other (OTH)

AF:

0.0710

AC:

150

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

431

862

1292

1723

2154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0558

Hom.:

Bravo

AF:

0.0704

Asia WGS

AF:

0.139

AC:

481

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abnormality of refraction

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Mutations in PAX6 can predispose to neonatal diabetes along with extra pancreatic manifestation of optic abnormalities. However, no sufficient evidence was found for the role of rs667773 variant in Diabetes Mellitus yet. -

carboxymethyl-dextran-A2-gadolinium-DOTA

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Aniridia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Foveal hypoplasia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

11p partial monosomy syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant keratitis

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19390808, 18776953, 12868034, 9727514, 27884173) -

Aniridia, Cerebellar Ataxia, And Intellectual Disability

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

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

-0.82

CADD

Benign

7.7

(source)

DANN

Benign

0.50

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over