rs139724326

Variant names:

• chr10-100750700-C-G
• rs139724326
• NM_000278.5:c.219C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-100750700-C-G
• chr10-100750700-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000278.5(PAX2):​c.219C>G​(p.Tyr73*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y73Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX2 NM_000278.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.947
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-100750700-C-G is Pathogenic according to our data. Variant chr10-100750700-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 562393.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX2	NM_000278.5	c.219C>G	p.Tyr73*	stop_gained	Exon 3 of 10	ENST00000355243.8	NP_000269.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX2	ENST00000355243.8	c.219C>G	p.Tyr73*	stop_gained	Exon 3 of 10	1	NM_000278.5	ENSP00000347385.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Renal coloboma syndrome Pathogenic:1

Nov 05, 2024

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

PAX2-related disorder Pathogenic:1

Jan 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PAX2 c.219C>G variant is predicted to result in premature protein termination (p.Tyr73*). This variant has been reported to be pathogenic for PAX2-related disorders (Bower et al. 2012. PubMed ID: 22213154; Groopman et al. 2018. PubMed ID: 30586318; Yang et al. 2021. PubMed ID: 34696790). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PAX2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		0.95
Vest4		0.92
GERP RS		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139724326; hg19: chr10-102510457;