10-100746267-A-T

Variant names:

• chr10-100746267-A-T
• rs780113818
• NM_000278.5:c.7A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000278.5(PAX2):​c.7A>T​(p.Met3Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAX2 NM_000278.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19651422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX2	NM_000278.5	c.7A>T	p.Met3Leu	missense_variant	Exon 1 of 10	ENST00000355243.8	NP_000269.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX2	ENST00000355243.8	c.7A>T	p.Met3Leu	missense_variant	Exon 1 of 10	1	NM_000278.5	ENSP00000347385.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248710 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461336 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.31	.;.;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.036
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	0.0	N;N;N;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.38	N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.46	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.012	B;B;B;.;.
Vest4		0.38
MutPred		0.22		Loss of catalytic residue at M3 (P = 0.0423);Loss of catalytic residue at M3 (P = 0.0423);Loss of catalytic residue at M3 (P = 0.0423);Loss of catalytic residue at M3 (P = 0.0423);Loss of catalytic residue at M3 (P = 0.0423);
MVP		0.81
MPC		1.4
ClinPred		0.27	T
GERP RS		4.8
Varity_R		0.30
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs780113818; hg19: chr10-102506024;