rs1894620

Positions:

• chr11-31812968-C-G
• chr11-31812968-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000638914.3(PAX6):​c.-316-1953G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,214 control chromosomes in the GnomAD database, including 2,934 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (2931 hom., cov: 31)
  • Exomes 𝑓: 0.10 (3 hom.)
• Consequence: PAX6 ENST00000638914.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.256

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]

PAUPAR (HGNC:49670): (PAX6 upstream antisense RNA) This gene is thought to produce a functional long non-coding RNA. Knockdown of this transcript results in genome-wide changes in gene expression, particularly of cell cyle genes, indicating a role in regulating differentiation. This transcript may bind to the promoter region of target genes and may also interact with the transcription factor Pax6 (paired box 6). [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001127612.3	c.-316-1953G>C		intron_variant			NP_001121084.1
PAX6	NM_001258462.3	c.-316-1953G>C		intron_variant			NP_001245391.1
PAX6	NM_001368919.2	c.-316-1953G>C		intron_variant			NP_001355848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000241001.13	c.-316-1953G>C		intron_variant		1		ENSP00000241001	P1
PAX6	ENST00000638914.3	c.-316-1953G>C		intron_variant		1		ENSP00000492315
PAX6	ENST00000639950.1	c.-713G>C		5_prime_UTR_variant	1/13	5		ENSP00000491862

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28345 AN: 152026 Hom.: 2925 Cov.: 31

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.100 AC: 7 AN: 70 Hom.: 3 Cov.: 0 AF XY: 0.100 AC XY: 5 AN XY: 50

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.187 AC: 28382 AN: 152144 Hom.: 2931 Cov.: 31 AF XY: 0.187 AC XY: 13944 AN XY: 74388

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.162

Alfa AF: 0.164 Hom.: 282

Bravo AF: 0.195

Asia WGS AF: 0.221 AC: 766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.7
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs1894620; hg19: chr11-31834516;