rs56139994

Variant names:

• chr11-31810819-C-T
• rs56139994
• NM_001368894.2:c.-129+9G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-31810819-C-T
• chr11-31810819-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001368894.2(PAX6):​c.-129+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 399,078 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (91 hom., cov: 33)
  • Exomes 𝑓: 0.038 (200 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.241
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 11-31810819-C-T is Benign according to our data. Variant chr11-31810819-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0301 (4578/152288) while in subpopulation NFE AF = 0.0424 (2881/68018). AF 95% confidence interval is 0.0411. There are 91 homozygotes in GnomAd4. There are 2178 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4578 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.-129+9G>A		intron	N/A	NP_001355823.1	P26367-2
	PAX6	NM_001368910.2		c.-29+9G>A		intron	N/A	NP_001355839.1
	PAX6	NM_001368911.2		c.13+9G>A		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.-129+9G>A		intron	N/A	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.-129+9G>A		intron	N/A	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.-129+9G>A		intron	N/A	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4581 AN: 152170 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0291

GnomAD4 exome AF: 0.0378 AC: 9323 AN: 246790 Hom.: 200 Cov.: 0 AF XY: 0.0381 AC XY: 4771 AN XY: 125092

African (AFR) AF: 0.00668 AC: 48 AN: 7182

American (AMR) AF: 0.0277 AC: 206 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 939 AN: 9240

East Asian (EAS) AF: 0.0000437 AC: 1 AN: 22894

South Asian (SAS) AF: 0.0109 AC: 33 AN: 3030

European-Finnish (FIN) AF: 0.0290 AC: 617 AN: 21270

Middle Eastern (MID) AF: 0.0417 AC: 54 AN: 1294

European-Non Finnish (NFE) AF: 0.0432 AC: 6835 AN: 158064

Other (OTH) AF: 0.0360 AC: 590 AN: 16382

GnomAD4 genome AF: 0.0301 AC: 4578 AN: 152288 Hom.: 91 Cov.: 33 AF XY: 0.0292 AC XY: 2178 AN XY: 74468

African (AFR) AF: 0.00722 AC: 300 AN: 41566

American (AMR) AF: 0.0299 AC: 458 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0128 AC: 62 AN: 4828

European-Finnish (FIN) AF: 0.0340 AC: 361 AN: 10608

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0424 AC: 2881 AN: 68018

Other (OTH) AF: 0.0284 AC: 60 AN: 2116

Alfa AF: 0.0398 Hom.: 193

Bravo AF: 0.0296

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	11p partial monosomy syndrome (1)
-	-	1	Aniridia 1 (1)
-	-	1	Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis (1)
-	-	1	Anophthalmia-microphthalmia syndrome (1)
-	-	1	Autosomal dominant keratitis (1)
-	-	1	carboxymethyl-dextran-A2-gadolinium-DOTA (1)
-	-	1	Congenital aniridia (1)
-	-	1	Foveal hypoplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		-0.24
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism

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: rs56139994; hg19: chr11-31832367;