rs75462234

Variant names:

• chr10-100749771-CG-C
• rs75462234
• NM_000278.5:c.76delG

Your query was ambiguous. Multiple possible variants found:

• 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.76delG​(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:9
• 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 60 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 rank	MANE	Protein	UniProt
PAX2	NM_000278.5	c.76delG	p.Val26CysfsTer3	frameshift_variant	Exon 2 of 10	ENST00000355243.8	NP_000269.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX2	ENST00000355243.8	c.76delG	p.Val26CysfsTer3	frameshift_variant	Exon 2 of 10	1	NM_000278.5	ENSP00000347385.3

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal coloboma syndrome Pathogenic:6

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.76del(p.Val26CysfsTer3) in PAX2 gene has been observed in heterozygous state in individual(s) with clinical features of PAX2-related conditions (Bekheirnia et. al., 2017; Heidet et. al., 2017). It is found to be segregating in disease related individuals (Bekheirnia et. al., 2017). This variant is also known as c.70delG (p.G24fs). The observed variant is absent in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Valine 26, changes this amino acid to Cysteine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Val26CysfsTer3. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX2 are known to be pathogenic (Barua et. al., 2014). For these reasons, this variant has been classified as Pathogenic. -

Jul 14, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 07, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006327 /PMID: 2358466 /3billion dataset).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 12815590, 16475226). A different missense change at the same codon (p.Gly324Val) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000458676 /PMID: 19006241). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 01, 2024

Department of Pediatrics, Seoul National University Bundang Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val26CysfsTer3 is a frameshirt variant and is regarded as pathogenic (PVS1, PM2, PP5, according to ACMG criteria). It has been reported in the following publications (PMID: 32203253, 10533062) -

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

Jul 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PAX2-related conditions (PMID: 27657687, 28566479). This variant is also known as c.70delG (p.G24fs). ClinVar contains an entry for this variant (Variation ID: 13801). For these reasons, this variant has been classified as Pathogenic. -

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PAX2-related disorder Pathogenic:1

Sep 13, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;