10-100746268-T-C

Variant names:

• chr10-100746268-T-C
• rs754968736
• NM_000278.5:c.8T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000278.5(PAX2):​c.8T>C​(p.Met3Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PAX2 NM_000278.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37
• Publications: 3 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4005033).

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.8T>C	p.Met3Thr	missense	Exon 1 of 10	NP_000269.3
	PAX2	NM_003990.5		c.8T>C	p.Met3Thr	missense	Exon 1 of 11	NP_003981.3
	PAX2	NM_001304569.2		c.101T>C	p.Met34Thr	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.8T>C	p.Met3Thr	missense	Exon 1 of 10	ENSP00000347385.3	Q02962-3
	PAX2	ENST00000370296.6	TSL:1	c.8T>C	p.Met3Thr	missense	Exon 1 of 11	ENSP00000359319.3	Q02962-4
	PAX2	ENST00000707079.1		c.8T>C	p.Met3Thr	missense	Exon 1 of 11	ENSP00000516730.1	A0A9L9PXU6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248708 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461366 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111646

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Renal coloboma syndrome;C4014925:Focal segmental glomerulosclerosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.20	N
PhyloP100		7.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.074	T
Polyphen		0.47	P
Vest4		0.49
MutPred		0.27		Loss of catalytic residue at M3 (P = 0.0171)
MVP		0.90
MPC		1.6
ClinPred		0.24	T
GERP RS		4.8
PromoterAI		0.014	Neutral
Varity_R		0.69
gMVP		0.83
Mutation Taster		=59/41	polymorphism

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: rs754968736; hg19: chr10-102506025;