rs41291450

Positions:

• chr10-100750841-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000278.5(PAX2):​c.360C>T​(p.Ala120=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,614,148 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (16 hom.)
• Consequence: PAX2 NM_000278.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -6.41

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-100750841-C-T is Benign according to our data. Variant chr10-100750841-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94386.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chr10-100750841-C-T is described in Lovd as [Benign]. Variant chr10-100750841-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00261 (398/152368) while in subpopulation NFE AF= 0.00422 (287/68034). AF 95% confidence interval is 0.00382. There are 2 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX2	NM_000278.5	c.360C>T	p.Ala120=	synonymous_variant	3/10	ENST00000355243.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX2	ENST00000355243.8	c.360C>T	p.Ala120=	synonymous_variant	3/10	1	NM_000278.5	P4

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 398 AN: 152250 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00288 AC: 724 AN: 251300 Hom.: 3 AF XY: 0.00267 AC XY: 363 AN XY: 135828

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00465

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00328 AC: 4789 AN: 1461780 Hom.: 16 Cov.: 32 AF XY: 0.00307 AC XY: 2229 AN XY: 727202

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152368 Hom.: 2 Cov.: 33 AF XY: 0.00248 AC XY: 185 AN XY: 74516

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00378 Hom.: 0

Bravo AF: 0.00236

EpiCase AF: 0.00365

EpiControl AF: 0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	PAX2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.15
DANN	Benign	0.86

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: rs41291450; hg19: chr10-102510598;