10-100746262-T-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_000278.5(PAX2):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000278.5 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248590Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134736
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461276Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727002
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: PAX2 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (p.Met3) is located in exon 1 of the encoded protein. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248590 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2T>A has been reported in the literature in an individual affected with congenital primary aphakia (e.g., Ernst_2022). This report does not provide unequivocal conclusions about association of the variant with PAX2-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35051625). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at