rs754146050
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2
The NM_000278.5(PAX2):c.220G>A(p.Glu74Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PAX2
NM_000278.5 missense
NM_000278.5 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 8.10
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 0 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000278.5
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.938
BS2
?
High AC in GnomAdExome4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX2 | NM_000278.5 | c.220G>A | p.Glu74Lys | missense_variant | 3/10 | ENST00000355243.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX2 | ENST00000355243.8 | c.220G>A | p.Glu74Lys | missense_variant | 3/10 | 1 | NM_000278.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251218Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135820
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461758Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727184
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renal coloboma syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 16, 2022 | This PAX2 variant (rs754146050) is rare (<0.1%) in a large population dataset (gnomAD: 2/282616 total alleles; 0.0007%; no homozygotes). It has been reported in ClinVar (Variation ID 1469446), but has not been reported in the literature, to our knowledge. Three bioinformatic tools queried predict that this substitution would be damaging, and glutamic acid at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of c.220G>A to be uncertain at this time. - |
Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2022 | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1469446). This variant has not been reported in the literature in individuals affected with PAX2-related conditions. This variant is present in population databases (rs754146050, gnomAD 0.008%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 74 of the PAX2 protein (p.Glu74Lys). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;.;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;D;.;.;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);.;Gain of MoRF binding (P = 0.0014);.;
MVP
MPC
2.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at