10-100749771-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000278.5(PAX2):c.76dup(p.Val26GlyfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L23L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PAX2 NM_000278.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:3
• 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 16 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 118 pathogenic variants in the truncated region.
• PP5: Variant 10-100749771-C-CG is Pathogenic according to our data. Variant chr10-100749771-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 156297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX2	NM_000278.5	c.76dup	p.Val26GlyfsTer28	frameshift_variant	2/10	ENST00000355243.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX2	ENST00000355243.8	c.76dup	p.Val26GlyfsTer28	frameshift_variant	2/10	1	NM_000278.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459260 Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3 AN XY: 725504

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: 0.0000946

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal coloboma syndrome Pathogenic:7 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 12, 2023	- -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 26, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift c.76dup p.Val26GlyfsTer28 variant in the PAX2 gene has been reported in individuals affected with Papillorenal syndrome Ohtsubo H et al., 2012. It has also been observed to segregate with disease in related individuals. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Valine 26, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Val26GlyfsTer28. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Frameshift variant c.69_70insG in Exon 2 of the PAX2 gene that results in the amino acid substitution p.Val26fs*28 was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 156297). This variant has been identified in individuals associated Papillorenal syndrome (Ohtsubo H et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -

not provided Pathogenic:5 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect in a mouse model for the variant exhibiting defects of the kidney, optic nerve, and retinal layer (Favor et al., 1996); This variant is associated with the following publications: (PMID: 23800802, 26489027, 24429398, 23539225, 22350371, 17541647, 21380624, 15808183, 8589702, 27226968, 20075965, 32164334, 10533062, 32203253, 33945118, 34217267, 32359821, 32604935, 33781268, 30937553, 31001663, 23966757, 8943028) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 07, 2018	- -

Focal segmental glomerulosclerosis 7 Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Precision Medicine Center, Zhengzhou University	-	PVS1:Null variant in the gene with established LOF as a disease mechanism PM2:at extremely low frequency in gnomAD PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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 (PVS1_VS). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (3billion dataset). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000156297, PMID:8589702, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 26, 2017	De novo variant in proband with FSGS, maternity and paternity confirmed (PS2). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 01, 2024	This sequence change in PAX2 is a frameshift variant predicted to cause a premature stop codon, p.(Val26Glyfs*28), in biologically relevant exon 2 of 11 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0003% (3/1,110,572 alleles) in the European (non-Finnish) population. This variant has been reported in multiple unrelated individuals with a phenotype consistent with PAX2-related renal disorders and is commonly de novo (PMID: 32203253). It has been identified as a de novo occurrence with confirmed parental relationships in at least one individual and as a de novo occurrence with unconfirmed parental relationships in multiple individuals with PAX2-related renal disorders (PMID: 34696790; 32203253, SCV000693891.1, SCV002059196.1). The variant has been reported to segregate with renal disorders in at least four individuals from two unrelated families (PMID: 32203253, 34696790). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS2/PM6_VeryStrong, PP1 -

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Val26Glyfs*28) 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, 35444690). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with PAX2-related disorders (PMID: 24429398, 27226968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156297). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 19, 2022	- -

PAX2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

The PAX2 c.76dupG variant is predicted to result in a frameshift and premature protein termination (p.Val26Glyfs*28). This variant has been reported in many individuals to be pathogenic for papillorenal syndrome, renal coloboma syndrome, and congenital anomalies of the kidney and urinary tract (Bower et al. 2012. PubMed ID: 22213154; c.69_70insG in Thomas et al. 2011. PubMed ID: 21380624; Iwafuchi et al. 2016. PubMed ID: 27226968; Sato et al. 2013. PubMed ID: 23966757; Madariaga et al. 2013. PubMed ID: 23539225). Individuals heterozygous for the c.76dup variant have highly variable clinical presentation and interfamilial variability is also observed (see for example Iwafuchi et al. 2016. PubMed ID: 27226968 and Sato et al. 2013. PubMed ID: 23966757). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-102509528-C-CG) and is reported in ClinVar by several outside labs as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/156297). Frameshift variants in PAX2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Congenital anomaly of kidney and urinary tract Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

May 27, 2019

This individual is heterozygous for a known pathogenic variant c.76dup (also known as 619insG) in the PAX2 gene. This frameshifting variant is predicted to create a premature stop codon p.(Val26Glyfs*28) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has been widely reported to be a papillorenal syndrome causing variant (OMIM * 167409; Bower et al Hum Mutat. 2012 Mar;33(3):457-66; Amiel et al Eur J Hum Genet. 2000 Nov;8(11):820-6). This variant is considered to be pathogenic according to the ACMG guidelines. -

Focal segmental glomerulosclerosis;C0403397:Steroid-resistant nephrotic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Apr 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs75462234; hg19: chr10-102509528;