10-100746273-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000278.5(PAX2):​c.13T>A​(p.Cys5Ser) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAX2
NM_000278.5 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.37
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAX2NM_000278.5 linkc.13T>A p.Cys5Ser missense_variant Exon 1 of 10 ENST00000355243.8 NP_000269.3 Q02962-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAX2ENST00000355243.8 linkc.13T>A p.Cys5Ser missense_variant Exon 1 of 10 1 NM_000278.5 ENSP00000347385.3 Q02962-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 Uncertain:1
Nov 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 5 of the PAX2 protein (p.Cys5Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAX2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
Pathogenic
0.57
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.72
.;.;D;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Benign
1.0
L;L;L;.;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-2.5
D;D;D;N;N
REVEL
Pathogenic
0.72
Sift
Benign
0.042
D;D;D;D;T
Sift4G
Benign
0.79
T;T;T;T;T
Polyphen
0.99
D;D;D;.;.
Vest4
0.75
MutPred
0.46
Loss of catalytic residue at M3 (P = 0.0025);Loss of catalytic residue at M3 (P = 0.0025);Loss of catalytic residue at M3 (P = 0.0025);Loss of catalytic residue at M3 (P = 0.0025);Loss of catalytic residue at M3 (P = 0.0025);
MVP
0.98
MPC
2.3
ClinPred
0.93
D
GERP RS
4.8
Varity_R
0.56
gMVP
0.95

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

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

Other links and lift over

dbSNP: rs904573203; hg19: chr10-102506030; API