NM_000486.6:c.785C>T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4
The NM_000486.6(AQP2):c.785C>T(p.Pro262Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000927 in 1,586,118 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P262S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000486.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AQP2 | NM_000486.6 | c.785C>T | p.Pro262Leu | missense_variant | Exon 4 of 4 | ENST00000199280.4 | NP_000477.1 | |
AQP5-AS1 | NR_110590.1 | n.257-1229G>A | intron_variant | Intron 1 of 2 | ||||
AQP5-AS1 | NR_110591.1 | n.118-3489G>A | intron_variant | Intron 1 of 2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152258Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000549 AC: 11AN: 200378Hom.: 0 AF XY: 0.0000633 AC XY: 7AN XY: 110614
GnomAD4 exome AF: 0.0000983 AC: 141AN: 1433860Hom.: 0 Cov.: 66 AF XY: 0.0000899 AC XY: 64AN XY: 712128
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152258Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74390
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 262 of the AQP2 protein (p.Pro262Leu). This variant is present in population databases (rs104894339, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive nephrogenic diabetes insipidus (PMID: 9550615, 15509592). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17844). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects AQP2 function (PMID: 9550615, 15509592, 18431594, 22778181, 27641679). For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate a damaging effect; the p.(P262L) variant results in increased localization to intracellular vesicles and basolateral membrane (PMID: 15509592, 28668390); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22778181, 27641679, 29799470, 19139070, 10564236, 15509592, 9550615, 28668390, 18431594, 26069764) -
Diabetes insipidus, nephrogenic, autosomal Pathogenic:2
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at