rs75462234

Positions:

• chr10-100749771-CG-C
• chr10-100749771-CG-CGG
• chr10-100749771-CG-CGGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000278.5(PAX2):​c.76del​(p.Val26CysfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAX2 NM_000278.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

Genes affected

PAX2 (HGNC:8616): (paired box 2) PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional supression by the tumor suppressor gene WT1. Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-100749771-CG-C is Pathogenic according to our data. Variant chr10-100749771-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 13801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100749771-CG-C is described in Lovd as [Pathogenic]. Variant chr10-100749771-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX2	NM_000278.5	c.76del	p.Val26CysfsTer3	frameshift_variant	2/10	ENST00000355243.8	NP_000269.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX2	ENST00000355243.8	c.76del	p.Val26CysfsTer3	frameshift_variant	2/10	1	NM_000278.5	ENSP00000347385	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459302 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal coloboma syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000013801 / PMID: 10466411). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -

Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13801). This variant is also known as c.70delG (p.G24fs). This premature translational stop signal has been observed in individual(s) with clinical features of PAX2-related conditions (PMID: 27657687, 28566479). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val26Cysfs*3) in the PAX2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX2 are known to be pathogenic (PMID: 11461952, 24676634). -

PAX2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 13, 2023

The PAX2 c.76del (p.Val26CysfsTer3) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. The p.Val26CysfsTer3 variant has been reported in a heterozygous state in at least six individuals with chronic kidney disease, renal malformations, and variable ocular phenotypes. The variant was confirmed de novo in three of these individuals and inherited from an affected parent in one individual (PMID: 21108633; 28566479; 32203253; 36549658). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant was identified in a de novo state. Based on the available evidence, the c.76del (p.Val26CysfsTer3) variant is classified as pathogenic for PAX2-related disorder. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75462234; hg19: chr10-102509528;