rs1800898

Positions:

• chr10-100809226-A-C
• chr10-100809226-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000278.5(PAX2):​c.909A>C​(p.Pro303=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,612,774 control chromosomes in the GnomAD database, including 81,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (15576 hom., cov: 32)
  • Exomes 𝑓: 0.29 (66047 hom.)
• Consequence: PAX2 NM_000278.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.735

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 10-100809226-A-C is Benign according to our data. Variant chr10-100809226-A-C is described in ClinVar as [Benign]. Clinvar id is 156300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100809226-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.735 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX2	NM_000278.5	c.909A>C	p.Pro303=	synonymous_variant	7/10	ENST00000355243.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX2	ENST00000355243.8	c.909A>C	p.Pro303=	synonymous_variant	7/10	1	NM_000278.5	P4

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59901 AN: 151992 Hom.: 15544 Cov.: 32

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.0939

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.364

GnomAD3 exomes AF: 0.281 AC: 70589 AN: 251066 Hom.: 12555 AF XY: 0.280 AC XY: 37976 AN XY: 135748

Gnomad AFR exome AF: 0.749

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.0986

Gnomad SAS exome AF: 0.323

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.282

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.287 AC: 419175 AN: 1460664 Hom.: 66047 Cov.: 34 AF XY: 0.287 AC XY: 208795 AN XY: 726666

Gnomad4 AFR exome AF: 0.763

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.307

GnomAD4 genome AF: 0.394 AC: 59982 AN: 152110 Hom.: 15576 Cov.: 32 AF XY: 0.385 AC XY: 28589 AN XY: 74338

Gnomad4 AFR AF: 0.742

Gnomad4 AMR AF: 0.275

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.0937

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.364

Alfa AF: 0.296 Hom.: 8204

Bravo AF: 0.416

Asia WGS AF: 0.251 AC: 874 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.299

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 36. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Renal coloboma syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Focal segmental glomerulosclerosis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.63
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800898; hg19: chr10-102568983; COSMIC: COSV62292939; COSMIC: COSV62292939;