10-100809115-C-A

Variant names:

• chr10-100809115-C-A
• rs1800897
• NM_000278.5:c.798C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000278.5(PAX2):​c.798C>A​(p.Asn266Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,526 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N266S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAX2 NM_000278.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• 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 3 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 renal coloboma syndrome, focal segmental glomerulosclerosis 7, familial idiopathic steroid-resistant nephrotic syndrome.

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.798C>A	p.Asn266Lys	missense	Exon 7 of 10	NP_000269.3
	PAX2	NM_003990.5		c.867C>A	p.Asn289Lys	missense	Exon 8 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.891C>A	p.Asn297Lys	missense	Exon 8 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.798C>A	p.Asn266Lys	missense	Exon 7 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.798C>A	p.Asn266Lys	missense	Exon 7 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000554172.2	TSL:1	c.786C>A	p.Asn262Lys	missense	Exon 6 of 7	ENSP00000452489.2	G3V5S4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460526 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110922

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.5	L
PhyloP100		-0.21
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Benign	0.94	T
Polyphen		0.26	B
Vest4		0.84
MutPred		0.27		Gain of ubiquitination at N289 (P = 0.0039)
MVP		0.89
MPC		0.50
ClinPred		0.35	T
GERP RS		-1.8
Varity_R		0.092
gMVP		0.64
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1800897; hg19: chr10-102568872;