10-100749771-CG-CGGG

Variant names:

• chr10-100749771-C-CGG
• rs75462234
• NM_000278.5:c.75_76dupGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000278.5(PAX2):​c.75_76dupGG​(p.Val26GlyfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX2 NM_000278.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 7

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• renal coloboma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 110 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-100749771-C-CGG is Pathogenic according to our data. Variant chr10-100749771-C-CGG is described in ClinVar as Pathogenic. ClinVar VariationId is 13802.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000278.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	NM_000278.5	MANE Select	c.75_76dupGG	p.Val26GlyfsTer4	frameshift	Exon 2 of 10	NP_000269.3
	PAX2	NM_003990.5		c.75_76dupGG	p.Val26GlyfsTer4	frameshift	Exon 2 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.168_169dupGG	p.Val57GlyfsTer4	frameshift	Exon 3 of 11	NP_001291498.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	ENST00000355243.8	TSL:1 MANE Select	c.75_76dupGG	p.Val26GlyfsTer4	frameshift	Exon 2 of 10	ENSP00000347385.3
	PAX2	ENST00000370296.6	TSL:1	c.75_76dupGG	p.Val26GlyfsTer4	frameshift	Exon 2 of 11	ENSP00000359319.3
	PAX2	ENST00000554172.2	TSL:1	c.87_88dupGG	p.Val30GlyfsTer4	frameshift	Exon 1 of 7	ENSP00000452489.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Renal coloboma syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs75462234; hg19: chr10-102509528;