rs114384476

Variant names:

• chr11-31801591-C-T
• rs114384476
• NM_001368894.2:c.369G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001368894.2(PAX6):​c.369G>A​(p.Glu123Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00191 in 1,614,150 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (37 hom.)
• Consequence: PAX6 NM_001368894.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.93
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-31801591-C-T is Benign according to our data. Variant chr11-31801591-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1618/152268) while in subpopulation AFR AF = 0.0377 (1567/41544). AF 95% confidence interval is 0.0362. There are 29 homozygotes in GnomAd4. There are 780 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1618 AD,Unknown gene.

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.369G>A	p.Glu123Glu	synonymous	Exon 7 of 14	NP_001355823.1	P26367-2
	PAX6	NM_001368910.2		c.570G>A	p.Glu190Glu	synonymous	Exon 7 of 14	NP_001355839.1
	PAX6	NM_001368911.2		c.372G>A	p.Glu124Glu	synonymous	Exon 4 of 10	NP_001355840.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000640368.2	TSL:5 MANE Select	c.369G>A	p.Glu123Glu	synonymous	Exon 7 of 14	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.369G>A	p.Glu123Glu	synonymous	Exon 7 of 14	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.369G>A	p.Glu123Glu	synonymous	Exon 7 of 14	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1613 AN: 152150 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00256 AC: 644 AN: 251484 AF XY: 0.00196

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00100 AC: 1465 AN: 1461882 Hom.: 37 Cov.: 32 AF XY: 0.000880 AC XY: 640 AN XY: 727242

African (AFR) AF: 0.0378 AC: 1264 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112000

Other (OTH) AF: 0.00225 AC: 136 AN: 60396

GnomAD4 genome AF: 0.0106 AC: 1618 AN: 152268 Hom.: 29 Cov.: 32 AF XY: 0.0105 AC XY: 780 AN XY: 74442

African (AFR) AF: 0.0377 AC: 1567 AN: 41544

American (AMR) AF: 0.00196 AC: 30 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00542 Hom.: 11

Bravo AF: 0.0118

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	11p partial monosomy syndrome (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.50
PhyloP100		4.9
Mutation Taster		=48/52	disease causing

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: rs114384476; hg19: chr11-31823139;