NM_001304569.2:c.13G>A

Variant names:

• chr10-100735721-G-A
• rs1287517556
• NM_001304569.2:c.13G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001304569.2(PAX2):​c.13G>A​(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX2 NM_001304569.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0520
• 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: Likely_benign. The variant received -1 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: 1.7657 (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.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304569.2. 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_001304569.2		c.13G>A	p.Ala5Thr	missense	Exon 1 of 11	NP_001291498.1	A0A9L9PYK3
	PAX2	NM_001374303.1		c.13G>A	p.Ala5Thr	missense	Exon 1 of 3	NP_001361232.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX2	ENST00000707078.1		c.13G>A	p.Ala5Thr	missense	Exon 1 of 11	ENSP00000516729.1	A0A9L9PYK3
	PAX2	ENST00000679374.1		c.13G>A	p.Ala5Thr	missense	Exon 1 of 10	ENSP00000506041.1	A0A7P0TAC9
	PAX2	ENST00000553492.5	TSL:4	n.119G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 896748 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 414272

African (AFR) AF: 0.00 AC: 0 AN: 18602

American (AMR) AF: 0.00 AC: 0 AN: 2822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9138

East Asian (EAS) AF: 0.00 AC: 0 AN: 13598

South Asian (SAS) AF: 0.00 AC: 0 AN: 17152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2022

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 800558

Other (OTH) AF: 0.00 AC: 0 AN: 32522

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.93
PhyloP100		-0.052
PromoterAI		0.035	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1287517556; hg19: chr10-102495478;