10-100749771-CG-CGG

Variant names:

• chr10-100749771-C-CG
• rs75462234
• NM_000278.5:c.76dupG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000278.5(PAX2):​c.76dupG​(p.Val26GlyfsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,260 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PAX2 NM_000278.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:3
• 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 16 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.
• PP5: Variant 10-100749771-C-CG is Pathogenic according to our data. Variant chr10-100749771-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 156297.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	NM_000278.5	MANE Select	c.76dupG	p.Val26GlyfsTer28	frameshift	Exon 2 of 10	NP_000269.3
	PAX2	NM_003990.5		c.76dupG	p.Val26GlyfsTer28	frameshift	Exon 2 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.169dupG	p.Val57GlyfsTer28	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.76dupG	p.Val26GlyfsTer28	frameshift	Exon 2 of 10	ENSP00000347385.3
	PAX2	ENST00000370296.6	TSL:1	c.76dupG	p.Val26GlyfsTer28	frameshift	Exon 2 of 11	ENSP00000359319.3
	PAX2	ENST00000554172.2	TSL:1	c.88dupG	p.Val30GlyfsTer28	frameshift	Exon 1 of 7	ENSP00000452489.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000283 AC: 7 AN: 246960 AF XY: 0.00

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459260 Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3 AN XY: 725504

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86014

European-Finnish (FIN) AF: 0.0000946 AC: 5 AN: 52876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110572

Other (OTH) AF: 0.00 AC: 0 AN: 60296

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000501289), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Renal coloboma syndrome (11)
6	-	-	Focal segmental glomerulosclerosis 7 (6)
5	-	-	not provided (6)
3	-	-	Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (3)
1	-	-	Congenital anomaly of kidney and urinary tract (1)
1	-	-	Focal segmental glomerulosclerosis;C0403397:Steroid-resistant nephrotic syndrome (1)
1	-	-	Glomerular sclerosis (1)
1	-	-	PAX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs75462234; hg19: chr10-102509528; COSMIC: COSV62290771;