NM_001304569.2:c.13G>T

Variant names:

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

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>T​(p.Ala5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign 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. A5T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX2 NM_001304569.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 2 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=-0.71).

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>T	p.Ala5Ser	missense	Exon 1 of 11	NP_001291498.1	A0A9L9PYK3
	PAX2	NM_001374303.1		c.13G>T	p.Ala5Ser	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>T	p.Ala5Ser	missense	Exon 1 of 11	ENSP00000516729.1	A0A9L9PYK3
	PAX2	ENST00000679374.1		c.13G>T	p.Ala5Ser	missense	Exon 1 of 10	ENSP00000506041.1	A0A7P0TAC9
	PAX2	ENST00000553492.5	TSL:4	n.119G>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

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 AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.9
DANN	Benign	0.84
PhyloP100		-0.052
PromoterAI		0.050	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;