Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 10.0

Publications

8 publications found

Variant links:

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]

PAX2 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 7
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
renal coloboma syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PAX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 110 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 VariationId is 13801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000278.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PAX2	NM_000278.5	MANE Select	c.76delG	p.Val26CysfsTer3	frameshift	Exon 2 of 10	NP_000269.3
PAX2	NM_003990.5		c.76delG	p.Val26CysfsTer3	frameshift	Exon 2 of 11	NP_003981.3
PAX2	NM_001304569.2		c.169delG	p.Val57CysfsTer3	frameshift	Exon 3 of 11	NP_001291498.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PAX2	ENST00000355243.8	TSL:1 MANE Select	c.76delG	p.Val26CysfsTer3	frameshift	Exon 2 of 10	ENSP00000347385.3
PAX2	ENST00000370296.6	TSL:1	c.76delG	p.Val26CysfsTer3	frameshift	Exon 2 of 11	ENSP00000359319.3
PAX2	ENST00000554172.2	TSL:1	c.88delG	p.Val30CysfsTer3	frameshift	Exon 1 of 7	ENSP00000452489.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459302

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725536

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110576

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal coloboma syndrome (7)

Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (2)

Focal segmental glomerulosclerosis 7 (1)

not provided (1)

PAX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over