chr10-100746286-C-T

Variant names:

• chr10-100746286-C-T
• rs2133823571
• NM_000278.5:c.26C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000278.5(PAX2):​c.26C>T​(p.Pro9Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P9R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PAX2 NM_000278.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 familial idiopathic steroid-resistant nephrotic syndrome, renal coloboma syndrome, focal segmental glomerulosclerosis 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

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.26C>T	p.Pro9Leu	missense	Exon 1 of 10	NP_000269.3
	PAX2	NM_003990.5		c.26C>T	p.Pro9Leu	missense	Exon 1 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.119C>T	p.Pro40Leu	missense	Exon 2 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.26C>T	p.Pro9Leu	missense	Exon 1 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.26C>T	p.Pro9Leu	missense	Exon 1 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000707079.1		c.26C>T	p.Pro9Leu	missense	Exon 1 of 11	ENSP00000516730.1	A0A9L9PXU6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459622 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726290

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110010

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.0	L
PhyloP100		7.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T
Sift4G	Benign	0.080	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.49		Loss of disorder (P = 0.0127)
MVP		0.97
MPC		1.4
ClinPred		0.96	D
GERP RS		4.8
PromoterAI		0.019	Neutral
Varity_R		0.38
gMVP		0.93
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs2133823571; hg19: chr10-102506043;