rs201383632

Variant names:

• chr10-100779565-G-A
• rs201383632
• NM_000278.5:c.478G>A
• PAX2 p.Ala160Thr

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 BP4_Strong BS1 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
• Publications: 5 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, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.4895 (below the threshold of 3.09). Trascript score misZ: 1.8687 (below the threshold of 3.09). GenCC associations: The gene is linked to renal coloboma syndrome, focal segmental glomerulosclerosis 7, familial idiopathic steroid-resistant nephrotic syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.055685163).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 75 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 10 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	NM_000278.5	MANE Select	c.478G>A	p.Ala160Thr	missense	Exon 4 of 10	NP_000269.3
	PAX2	NM_003990.5		c.478G>A	p.Ala160Thr	missense	Exon 4 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.571G>A	p.Ala191Thr	missense	Exon 5 of 11	NP_001291498.1	A0A9L9PYK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	ENST00000355243.8	TSL:1 MANE Select	c.478G>A	p.Ala160Thr	missense	Exon 4 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.478G>A	p.Ala160Thr	missense	Exon 4 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000554172.2	TSL:1	c.490G>A	p.Ala164Thr	missense	Exon 3 of 7	ENSP00000452489.2	G3V5S4

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

GnomAD2 exomes AF: 0.000134 AC: 28 AN: 208830 AF XY: 0.000126

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 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

African (AFR) AF: 0.0000902 AC: 3 AN: 33270

American (AMR) AF: 0.0000971 AC: 4 AN: 41182

Ashkenazi Jewish (ASJ) AF: 0.000235 AC: 6 AN: 25510

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38920

South Asian (SAS) AF: 0.000244 AC: 20 AN: 81890

European-Finnish (FIN) AF: 0.0000194 AC: 1 AN: 51498

Middle Eastern (MID) AF: 0.00768 AC: 44 AN: 5726

European-Non Finnish (NFE) AF: 0.0000527 AC: 58 AN: 1100076

Other (OTH) AF: 0.000235 AC: 14 AN: 59538

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

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.0034
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.056	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	-0.29	N
PhyloP100		4.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.31
Sift	Benign	0.39	T
Sift4G	Benign	0.33	T
Varity_R		0.080
gMVP		0.59
Mutation Taster		=94/6	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201383632;

hg19: chr10-102539322;