rs201383632

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000278.5(PAX2):c.478G>A(p.Ala160Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000101 in 1,589,888 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

PAX2
NM_000278.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.93

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.055685163).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000105 (151/1437610) while in subpopulation MID AF= 0.00768 (44/5726). AF 95% confidence interval is 0.00588. There are 1 homozygotes in gnomad4_exome. There are 75 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX2	NM_000278.5 link	c.478G>A	p.Ala160Thr	missense_variant	Exon 4 of 10	ENST00000355243.8	NP_000269.3	Q02962-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX2	ENST00000355243.8 link	c.478G>A	p.Ala160Thr	missense_variant	Exon 4 of 10	1	NM_000278.5	ENSP00000347385.3		Q02962-3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000134

AC:

AN:

208830

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

111494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000998

Gnomad ASJ exome

AF:

0.000329

Gnomad EAS exome

AF:

0.0000624

Gnomad SAS exome

AF:

0.000156

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.000105

AC:

151

AN:

1437610

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

712376

show subpopulations

Gnomad4 AFR exome

AF:

0.0000902

Gnomad4 AMR exome

AF:

0.0000971

Gnomad4 ASJ exome

AF:

0.000235

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.0000527

Gnomad4 OTH exome

AF:

0.000235

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2019	- -

Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 20, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 160 of the PAX2 protein (p.Ala160Thr). This variant is present in population databases (rs201383632, gnomAD 0.03%). This missense change has been observed in individual(s) with renal coloboma syndrome and was also identified in the individual's unaffected mother (PMID: 22213154). ClinVar contains an entry for this variant (Variation ID: 569063). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

.;.;T;.;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.0034

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

T;T;T;T;T;T

MetaRNN

Benign

0.056

T;T;T;T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

-0.29

N;N;N;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.64

N;N;N;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.39

T;T;T;.;T;T

Sift4G

Benign

0.33

T;T;T;T;T;T

Polyphen

0.013

B;B;B;.;.;B

Vest4

0.16

MVP

0.85

MPC

0.30

ClinPred

0.040

GERP RS

4.8

Varity_R

0.080

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over