rs104894333
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000486.6(AQP2):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 1,599,382 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.
Frequency
Consequence
NM_000486.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AQP2 | NM_000486.6 | c.374C>T | p.Thr125Met | missense_variant | 2/4 | ENST00000199280.4 | |
AQP5-AS1 | NR_110591.1 | n.118-2080G>A | intron_variant, non_coding_transcript_variant | ||||
AQP5-AS1 | NR_110590.1 | n.437G>A | non_coding_transcript_exon_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AQP2 | ENST00000199280.4 | c.374C>T | p.Thr125Met | missense_variant | 2/4 | 1 | NM_000486.6 | P1 | |
AQP5-AS1 | ENST00000550530.1 | n.118-2080G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000827 AC: 2AN: 241708Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131410
GnomAD4 exome AF: 0.00000691 AC: 10AN: 1447050Hom.: 0 Cov.: 30 AF XY: 0.00000972 AC XY: 7AN XY: 720318
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152332Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74484
ClinVar
Submissions by phenotype
Diabetes insipidus, nephrogenic, autosomal Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10564236, 9550615, 9745427). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with AQP2 related disorder (ClinVar ID: VCV000017837 / PMID: 9745427). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 19293543, 30784238, 9550615, 9745427). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 19293543, 9550615, 9745427). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1998 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AQP2 function (PMID: 9550615, 10564236). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AQP2 protein function. ClinVar contains an entry for this variant (Variation ID: 17837). This missense change has been observed in individual(s) with autosomal recessive nephrogenic diabetes insipidus (PMID: 9550615, 19293543, 30784238). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894333, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the AQP2 protein (p.Thr125Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at