rs387906530

chr10-100750699-A-ACGAGAC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal coloboma syndrome Pathogenic:3

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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Aug 24, 2016	- -

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: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906530; hg19: chr10-102510456;