10-100746313-G-C

Position:

• chr10-100746313-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000278.5(PAX2):​c.43+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 1,576,532 control chromosomes in the GnomAD database, including 520,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48725 hom., cov: 33)
  • Exomes 𝑓: 0.81 (471896 hom.)
• Consequence: PAX2 NM_000278.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.77

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-100746313-G-C is Benign according to our data. Variant chr10-100746313-G-C is described in ClinVar as [Benign]. Clinvar id is 94387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100746313-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX2	NM_000278.5	c.43+10G>C		intron_variant		ENST00000355243.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX2	ENST00000355243.8	c.43+10G>C		intron_variant		1	NM_000278.5	P4

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121385 AN: 152074 Hom.: 48678 Cov.: 33

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.778

GnomAD3 exomes AF: 0.838 AC: 208401 AN: 248608 Hom.: 88091 AF XY: 0.840 AC XY: 113211 AN XY: 134724

Gnomad AFR exome AF: 0.749

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.792

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.924

Gnomad FIN exome AF: 0.861

Gnomad NFE exome AF: 0.797

Gnomad OTH exome AF: 0.815

GnomAD4 exome AF: 0.812 AC: 1157089 AN: 1424340 Hom.: 471896 Cov.: 28 AF XY: 0.815 AC XY: 579178 AN XY: 710880

Gnomad4 AFR exome AF: 0.737

Gnomad4 AMR exome AF: 0.850

Gnomad4 ASJ exome AF: 0.790

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.920

Gnomad4 FIN exome AF: 0.855

Gnomad4 NFE exome AF: 0.796

Gnomad4 OTH exome AF: 0.811

GnomAD4 genome AF: 0.798 AC: 121488 AN: 152192 Hom.: 48725 Cov.: 33 AF XY: 0.807 AC XY: 60031 AN XY: 74420

Gnomad4 AFR AF: 0.747

Gnomad4 AMR AF: 0.814

Gnomad4 ASJ AF: 0.794

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.919

Gnomad4 FIN AF: 0.863

Gnomad4 NFE AF: 0.793

Gnomad4 OTH AF: 0.781

Alfa AF: 0.779 Hom.: 5211

Bravo AF: 0.790

Asia WGS AF: 0.946 AC: 3289 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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 97% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 90. Only high quality variants are reported. -

Renal coloboma syndrome Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.87

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: rs4472867; hg19: chr10-102506070;