rs104894754
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000054.7(AVPR2):c.253G>A(p.Asp85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 26)
Consequence
AVPR2
NM_000054.7 missense
NM_000054.7 missense
Scores
6
4
2
Clinical Significance
Conservation
PhyloP100: 3.43
Genes affected
AVPR2 (HGNC:897): (arginine vasopressin receptor 2) This gene encodes the vasopressin receptor, type 2, also known as the V2 receptor, which belongs to the seven-transmembrane-domain G protein-coupled receptor (GPCR) superfamily, and couples to Gs thus stimulating adenylate cyclase. The subfamily that includes the V2 receptor, the V1a and V1b vasopressin receptors, the oxytocin receptor, and isotocin and mesotocin receptors in non-mammals, is well conserved, though several members signal via other G proteins. All bind similar cyclic nonapeptide hormones. The V2 receptor is expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, where its primary property is to respond to the pituitary hormone arginine vasopressin (AVP) by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of this gene is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results. The V2 receptor is also expressed outside the kidney although its tissue localization is uncertain. When these 'extrarenal receptors' are stimulated by infusion of a V2 selective agonist (dDAVP), a variety of clotting factors are released into the bloodstream. The physiologic importance of this property is not known - its absence does not appear to be detrimental in NDI patients. The gene expression has also been described in fetal lung tissue and lung cancer associated with alternative splicing. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a transmembrane_region Helical; Name=2 (size 20) in uniprot entity V2R_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000054.7
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
?
Variant X-153905759-G-A is Pathogenic according to our data. Variant chrX-153905759-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10845.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153905759-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AVPR2 | NM_000054.7 | c.253G>A | p.Asp85Asn | missense_variant | 3/4 | ENST00000646375.2 | |
AVPR2 | NM_001146151.3 | c.253G>A | p.Asp85Asn | missense_variant | 3/3 | ||
AVPR2 | NR_027419.2 | n.466-260G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AVPR2 | ENST00000646375.2 | c.253G>A | p.Asp85Asn | missense_variant | 3/4 | NM_000054.7 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 26
GnomAD3 genomes
?
Cov.:
26
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome ? Cov.: 26
GnomAD4 genome
?
Cov.:
26
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Diabetes insipidus, nephrogenic, X-linked Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1997 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20459358, 7933835, 32073219, 34101133, 23600372) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;D;.
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;H;H
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
Polyphen
D;D;.;D;D
Vest4
0.95, 0.95, 0.91
MutPred
Loss of stability (P = 0.1495);Loss of stability (P = 0.1495);Loss of stability (P = 0.1495);Loss of stability (P = 0.1495);Loss of stability (P = 0.1495);
MVP
1.0
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at