rs104894760
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000054.7(AVPR2):c.310C>T(p.Arg104Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,092,691 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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. R104H) has been classified as Benign.
Frequency
Consequence
NM_000054.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AVPR2 | NM_000054.7 | c.310C>T | p.Arg104Cys | missense_variant | 3/4 | ENST00000646375.2 | |
AVPR2 | NM_001146151.3 | c.310C>T | p.Arg104Cys | missense_variant | 3/3 | ||
AVPR2 | NR_027419.2 | n.466-203C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AVPR2 | ENST00000646375.2 | c.310C>T | p.Arg104Cys | missense_variant | 3/4 | NM_000054.7 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD4 exome AF: 0.00000183 AC: 2AN: 1092691Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 361287
GnomAD4 genome ? Cov.: 25
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 104 of the AVPR2 protein (p.Arg104Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nephrogenic diabetes insipidus (PMID: 11232028, 14709855, 34101133). ClinVar contains an entry for this variant (Variation ID: 10853). 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 expected to disrupt AVPR2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AVPR2 function (PMID: 11232028, 19812297). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Diabetes insipidus, nephrogenic, X-linked Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Diabetes insipidus, nephrogenic, X-linked;C1845202:Nephrogenic syndrome of inappropriate antidiuresis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Nephrogenic diabetes insipidus Other:1
not provided, no classification provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at