rs201383632

Positions:

• chr10-100779565-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000278.5(PAX2):​c.478G>A​(p.Ala160Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000101 in 1,589,888 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PAX2 NM_000278.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.93

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055685163).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000105 (151/1437610) while in subpopulation MID AF= 0.00768 (44/5726). AF 95% confidence interval is 0.00588. There are 1 homozygotes in gnomad4_exome. There are 75 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX2	NM_000278.5	c.478G>A	p.Ala160Thr	missense_variant	4/10	ENST00000355243.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX2	ENST00000355243.8	c.478G>A	p.Ala160Thr	missense_variant	4/10	1	NM_000278.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000134 AC: 28 AN: 208830 Hom.: 0 AF XY: 0.000126 AC XY: 14 AN XY: 111494

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000998

Gnomad ASJ exome AF: 0.000329

Gnomad EAS exome AF: 0.0000624

Gnomad SAS exome AF: 0.000156

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.000105 AC: 151 AN: 1437610 Hom.: 1 Cov.: 31 AF XY: 0.000105 AC XY: 75 AN XY: 712376

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.0000971

Gnomad4 ASJ exome AF: 0.000235

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000527

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2019	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 160 of the PAX2 protein (p.Ala160Thr). This variant is present in population databases (rs201383632, gnomAD 0.03%). This missense change has been observed in individual(s) with renal coloboma syndrome and was also identified in the individual's unaffected mother (PMID: 22213154). ClinVar contains an entry for this variant (Variation ID: 569063). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;.;T;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.0034
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;T;T;T;T;T
MetaRNN	Benign	0.056	T;T;T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	-0.29	N;N;N;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.64	N;N;N;.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.39	T;T;T;.;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T
Polyphen		0.013	B;B;B;.;.;B
Vest4		0.16
MVP		0.85
MPC		0.30
ClinPred		0.040	T
GERP RS		4.8
Varity_R		0.080
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201383632; hg19: chr10-102539322;