rs193922112
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000054.7(AVPR2):āc.176T>Cā(p.Leu59Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,113 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 (ā ).
Frequency
Genomes: not found (cov: 26)
Exomes š: 9.1e-7 ( 0 hom. 0 hem. )
Consequence
AVPR2
NM_000054.7 missense
NM_000054.7 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 5.77
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 Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant X-153905682-T-C is Pathogenic according to our data. Variant chrX-153905682-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35737.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153905682-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AVPR2 | NM_000054.7 | c.176T>C | p.Leu59Pro | missense_variant | 3/4 | ENST00000646375.2 | NP_000045.1 | |
AVPR2 | NM_001146151.3 | c.176T>C | p.Leu59Pro | missense_variant | 3/3 | NP_001139623.1 | ||
AVPR2 | NR_027419.2 | n.466-337T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AVPR2 | ENST00000646375.2 | c.176T>C | p.Leu59Pro | missense_variant | 3/4 | NM_000054.7 | ENSP00000496396 | P1 |
Frequencies
GnomAD3 genomes Cov.: 26
GnomAD3 genomes
Cov.:
26
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097113Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 362959
GnomAD4 exome
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1
AN:
1097113
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35
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0
AN XY:
362959
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 26
GnomAD4 genome
Cov.:
26
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nephrogenic diabetes insipidus Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;D;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;.;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;D;D;D
Sift4G
Pathogenic
.;D;D;D;D
Polyphen
D;D;.;D;D
Vest4
0.95, 0.95, 0.94
MutPred
Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);
MVP
1.0
MPC
1.8
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