11-31811994-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000638914.3(PAX6):c.-316-979G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,540 control chromosomes in the GnomAD database, including 2,576 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 0.18 ( 2572 hom., cov: 32)

Exomes 𝑓: 0.15 ( 4 hom. )

Consequence

PAX6
ENST00000638914.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.812

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000638914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
PAX6	NM_001368915.2	c.-503G>C	5_prime_UTR	Exon 1 of 12	NP_001355844.1
PAX6	NM_001368887.2	c.-503G>C	5_prime_UTR	Exon 1 of 13	NP_001355816.1
PAX6	NM_001368919.2	c.-316-979G>C	intron	N/A	NP_001355848.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PAX6	ENST00000638914.3	TSL:1	c.-316-979G>C	intron	N/A	ENSP00000492315.2
PAX6	ENST00000639409.1	TSL:1	c.-317+99G>C	intron	N/A	ENSP00000492476.1
PAX6	ENST00000640975.1	TSL:1	c.-317+155G>C	intron	N/A	ENSP00000491872.1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26941

AN:

152118

Hom.:

2570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.300

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.159

GnomAD4 exome

AF:

0.155

AC:

AN:

304

Hom.:

Cov.:

AF XY:

0.161

AC XY:

AN XY:

236

show subpopulations

African (AFR)

AF:

0.167

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

AN:

East Asian (EAS)

AF:

0.450

AC:

AN:

South Asian (SAS)

AF:

0.333

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.118

AC:

AN:

246

Other (OTH)

AF:

0.200

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.177

AC:

26974

AN:

152236

Hom.:

2572

Cov.:

AF XY:

0.177

AC XY:

13177

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.226

AC:

9385

AN:

41538

American (AMR)

AF:

0.196

AC:

2991

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

389

AN:

3472

East Asian (EAS)

AF:

0.300

AC:

1546

AN:

5156

South Asian (SAS)

AF:

0.184

AC:

887

AN:

4828

European-Finnish (FIN)

AF:

0.152

AC:

1608

AN:

10596

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9686

AN:

68026

Other (OTH)

AF:

0.157

AC:

333

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1142

2284

3426

4568

5710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<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:

0.0770

Hom.:

100

Bravo

AF:

0.183

Asia WGS

AF:

0.220

AC:

762

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.9

(source)

DANN

Benign

0.68

PhyloP100

-0.81

PromoterAI

-0.13

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over