chr11-31794348-T-C

Variant names:

• chr11-31794348-T-C
• rs2239789
• NM_001368894.2:c.725-234A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001368894.2(PAX6):​c.725-234A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000909 (42/461938) while in subpopulation EAS AF = 0.00136 (42/30906). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAdExome4. There are 23 alleles in the male GnomAdExome4 subpopulation. Median coverage is 3. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 42 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.725-234A>G		intron	N/A	NP_001355823.1	P26367-2
	PAX6	NM_001368910.2		c.926-234A>G		intron	N/A	NP_001355839.1
	PAX6	NM_001368911.2		c.728-234A>G		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.725-234A>G		intron	N/A	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.725-234A>G		intron	N/A	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.725-234A>G		intron	N/A	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151216 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000909 AC: 42 AN: 461938 Hom.: 0 Cov.: 3 AF XY: 0.0000935 AC XY: 23 AN XY: 245978

African (AFR) AF: 0.00 AC: 0 AN: 12784

American (AMR) AF: 0.00 AC: 0 AN: 20220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14008

East Asian (EAS) AF: 0.00136 AC: 42 AN: 30906

South Asian (SAS) AF: 0.00 AC: 0 AN: 46428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3434

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 278536

Other (OTH) AF: 0.00 AC: 0 AN: 26560

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151216 Hom.: 0 Cov.: 29 AF XY: 0.0000136 AC XY: 1 AN XY: 73742

African (AFR) AF: 0.00 AC: 0 AN: 41016

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 2226

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.3
DANN	Benign	0.70
PhyloP100		-0.39

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: rs2239789; hg19: chr11-31815896;