10-100750699-A-ACGAGAC
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4PP5_Very_Strong
The NM_000278.5(PAX2):c.221_226dup(p.Glu74_Thr75dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y73Y) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
PAX2
NM_000278.5 inframe_insertion
NM_000278.5 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.947
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 Pathogenic. Variant got 14 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, 6 uncertain in NM_000278.5
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000278.5.
PP5
Variant 10-100750699-A-ACGAGAC is Pathogenic according to our data. Variant chr10-100750699-A-ACGAGAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX2 | NM_000278.5 | c.221_226dup | p.Glu74_Thr75dup | inframe_insertion | 3/10 | ENST00000355243.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX2 | ENST00000355243.8 | c.221_226dup | p.Glu74_Thr75dup | inframe_insertion | 3/10 | 1 | NM_000278.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renal coloboma syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Aug 24, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | research | Precision Medicine Center, Zhengzhou University | - | PM1:Located in a mutational hot spot PM2:not found in gnomAD PM4:Protein length changes as a result of in-frame deletions PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product - |
Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects PAX2 function (PMID: 20221250). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 13800). This variant has been observed in individual(s) with papillorenal syndrome (PMID: 9760197, 29054766). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This variant, c.221_226dup, results in the insertion of 2 amino acid(s) to the PAX2 protein (p.Glu74_Thr75dup), but otherwise preserves the integrity of the reading frame. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at