NM_001368894.2:c.1075-174G>A

Variant names:

• chr11-31791034-C-T
• rs2071754
• NM_001368894.2:c.1075-174G>A

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.1075-174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 762,266 control chromosomes in the GnomAD database, including 215,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37626 hom., cov: 32)
  • Exomes 𝑓: 0.76 (177969 hom.)
• Consequence: PAX6 NM_001368894.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.655
• Publications: 20 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-31791034-C-T is Benign according to our data. Variant chr11-31791034-C-T is described in ClinVar as Benign. ClinVar VariationId is 674009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.1075-174G>A		intron_variant	Intron 12 of 13	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.1075-174G>A		intron_variant	Intron 12 of 13	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104691 AN: 151948 Hom.: 37613 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.870

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.712

GnomAD4 exome AF: 0.757 AC: 461623 AN: 610200 Hom.: 177969 Cov.: 7 AF XY: 0.762 AC XY: 248946 AN XY: 326622

African (AFR) AF: 0.511 AC: 8589 AN: 16824

American (AMR) AF: 0.557 AC: 19174 AN: 34452

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 15619 AN: 20104

East Asian (EAS) AF: 0.492 AC: 15671 AN: 31834

South Asian (SAS) AF: 0.759 AC: 47877 AN: 63094

European-Finnish (FIN) AF: 0.769 AC: 26233 AN: 34108

Middle Eastern (MID) AF: 0.754 AC: 2615 AN: 3470

European-Non Finnish (NFE) AF: 0.808 AC: 302316 AN: 374242

Other (OTH) AF: 0.734 AC: 23529 AN: 32072

GnomAD4 genome AF: 0.689 AC: 104736 AN: 152066 Hom.: 37626 Cov.: 32 AF XY: 0.687 AC XY: 51052 AN XY: 74344

African (AFR) AF: 0.498 AC: 20647 AN: 41438

American (AMR) AF: 0.642 AC: 9820 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2726 AN: 3468

East Asian (EAS) AF: 0.487 AC: 2510 AN: 5156

South Asian (SAS) AF: 0.751 AC: 3615 AN: 4816

European-Finnish (FIN) AF: 0.772 AC: 8170 AN: 10584

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.805 AC: 54745 AN: 68000

Other (OTH) AF: 0.715 AC: 1509 AN: 2110

Alfa AF: 0.762 Hom.: 84895

Bravo AF: 0.667

Asia WGS AF: 0.605 AC: 2106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.3
DANN	Benign	0.83
PhyloP100		0.66
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: rs2071754; hg19: chr11-31812582;