10-100749771-C-CG

Variant names:

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

Variant summary

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

The NM_000278.5(PAX2):​c.76dupG​(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 (★★).

• 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:25 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 60 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 rank	MANE	Protein	UniProt
PAX2	NM_000278.5	c.76dupG	p.Val26GlyfsTer28	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.76dupG	p.Val26GlyfsTer28	frameshift_variant	Exon 2 of 10	1	NM_000278.5	ENSP00000347385.3

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:25 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal coloboma syndrome Pathogenic:7 Other:2

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 26, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Nov 12, 2023

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 10, 2023

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Focal segmental glomerulosclerosis 7 Pathogenic:6

Aug 05, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Sep 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

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 26, 2017

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

De novo variant in proband with FSGS, maternity and paternity confirmed (PS2). -

-

Precision Medicine Center, Zhengzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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 -

not provided Pathogenic:5 Other:1

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 07, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 Pathogenic:3

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS2_Moderate+PS4_Supporting+PP4 -

Oct 02, 2024

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.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. -

May 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PAX2-related disorder Pathogenic:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 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

May 27, 2019

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Glomerular sclerosis Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PS2,PP1,PM2 -

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

Apr 17, 2019

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;