chr10-100749889-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000278.5(PAX2):​c.187G>A​(p.Gly63Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G63D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PAX2
NM_000278.5 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000278.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 10-100749889-G-A is Pathogenic according to our data. Variant chr10-100749889-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217287.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-100749889-G-A is described in Lovd as [Pathogenic]. Variant chr10-100749889-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAX2NM_000278.5 linkuse as main transcriptc.187G>A p.Gly63Ser missense_variant 2/10 ENST00000355243.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAX2ENST00000355243.8 linkuse as main transcriptc.187G>A p.Gly63Ser missense_variant 2/101 NM_000278.5 P4Q02962-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterresearchDivision of Blood Purification, Kakanzawa University’Oct 19, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
.;.;D;.;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
M;M;M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.9
D;D;D;.;D;D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;D;D;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;D;D;.;.;D
Vest4
0.94
MutPred
0.94
Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);.;
MVP
0.99
MPC
2.6
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.95
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886037755; hg19: chr10-102509646; API