chr11-31790667-A-C

Variant names:

• chr11-31790667-A-C
• rs3026393
• NM_001368894.2:c.1225+43T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001368894.2(PAX6):​c.1225+43T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 1,612,374 control chromosomes in the GnomAD database, including 204,943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15850 hom., cov: 32)
  • Exomes 𝑓: 0.51 (189093 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.471
• Publications: 30 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=-0.83).
• BP6: Variant 11-31790667-A-C is Benign according to our data. Variant chr11-31790667-A-C is described in ClinVar as Benign. ClinVar VariationId is 1283019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

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.1225+43T>G		intron	N/A	NP_001355823.1	P26367-2
	PAX6	NM_001368910.2		c.1426+43T>G		intron	N/A	NP_001355839.1
	PAX6	NM_001368911.2		c.1078-648T>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.1225+43T>G		intron	N/A	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.1225+43T>G		intron	N/A	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.1225+43T>G		intron	N/A	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67978 AN: 151954 Hom.: 15834 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.480 AC: 120157 AN: 250416 AF XY: 0.494

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.347

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.489

GnomAD4 exome AF: 0.506 AC: 738371 AN: 1460302 Hom.: 189093 Cov.: 34 AF XY: 0.510 AC XY: 370788 AN XY: 726452

African (AFR) AF: 0.315 AC: 10534 AN: 33468

American (AMR) AF: 0.356 AC: 15910 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12305 AN: 26116

East Asian (EAS) AF: 0.459 AC: 18219 AN: 39688

South Asian (SAS) AF: 0.597 AC: 51511 AN: 86222

European-Finnish (FIN) AF: 0.473 AC: 24986 AN: 52770

Middle Eastern (MID) AF: 0.493 AC: 2835 AN: 5752

European-Non Finnish (NFE) AF: 0.515 AC: 572629 AN: 1111194

Other (OTH) AF: 0.488 AC: 29442 AN: 60372

GnomAD4 genome AF: 0.447 AC: 68015 AN: 152072 Hom.: 15850 Cov.: 32 AF XY: 0.447 AC XY: 33234 AN XY: 74324

African (AFR) AF: 0.318 AC: 13217 AN: 41504

American (AMR) AF: 0.412 AC: 6307 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1676 AN: 3472

East Asian (EAS) AF: 0.456 AC: 2355 AN: 5164

South Asian (SAS) AF: 0.588 AC: 2831 AN: 4812

European-Finnish (FIN) AF: 0.471 AC: 4967 AN: 10546

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35094 AN: 67966

Other (OTH) AF: 0.484 AC: 1022 AN: 2112

Alfa AF: 0.460 Hom.: 8687

Bravo AF: 0.433

Asia WGS AF: 0.507 AC: 1766 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.63
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs3026393; hg19: chr11-31812215; COSMIC: COSV53794877; COSMIC: COSV53794877;