NM_000278.5:c.221_226dupAGACCG

Variant names:

• chr10-100750699-A-ACGAGAC
• rs387906530
• NM_000278.5:c.221_226dupAGACCG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_000278.5(PAX2):​c.221_226dupAGACCG​(p.Glu74_Thr75dup) variant causes a disruptive 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX2 NM_000278.5 disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.947
• Publications: 2 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, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 13800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	NM_000278.5	MANE Select	c.221_226dupAGACCG	p.Glu74_Thr75dup	disruptive_inframe_insertion	Exon 3 of 10	NP_000269.3
	PAX2	NM_003990.5		c.221_226dupAGACCG	p.Glu74_Thr75dup	disruptive_inframe_insertion	Exon 3 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.314_319dupAGACCG	p.Glu105_Thr106dup	disruptive_inframe_insertion	Exon 4 of 11	NP_001291498.1	A0A9L9PYK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	ENST00000355243.8	TSL:1 MANE Select	c.221_226dupAGACCG	p.Glu74_Thr75dup	disruptive_inframe_insertion	Exon 3 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.221_226dupAGACCG	p.Glu74_Thr75dup	disruptive_inframe_insertion	Exon 3 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000554172.2	TSL:1	c.233_238dupAGACCG	p.Glu78_Thr79dup	disruptive_inframe_insertion	Exon 2 of 7	ENSP00000452489.2	G3V5S4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Renal coloboma syndrome (3)
2	-	-	Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.95
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs387906530; hg19: chr10-102510456;