rs28935496

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000054.7(AVPR2):c.337C>T(p.Arg113Trp) 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)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

AVPR2
NM_000054.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.135

Variant links:

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]

AVPR2 links:

ENSG00000284987 (HGNC:):

ENSG00000284987 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Extracellular (size 14) in uniprot entity V2R_HUMAN there are 5 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, 0.981

PP5

Variant X-153905843-C-T is Pathogenic according to our data. Variant chrX-153905843-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153905843-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7 link	c.337C>T	p.Arg113Trp	missense_variant	Exon 3 of 4	ENST00000646375.2	NP_000045.1	P30518-1
AVPR2	NM_001146151.3 link	c.337C>T	p.Arg113Trp	missense_variant	Exon 3 of 3		NP_001139623.1	P30518-2
AVPR2	NR_027419.2 link	n.466-176C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2 link	c.337C>T	p.Arg113Trp	missense_variant	Exon 3 of 4		NM_000054.7	ENSP00000496396.1		P30518-1
ENSG00000284987	ENST00000646191.1 link	n.96+3227G>A		intron_variant	Intron 1 of 4			ENSP00000493873.1		A0A2R8Y4P6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000563

AC:

AN:

177487

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65413

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000918

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1091444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360992

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diabetes insipidus, nephrogenic, X-linked

Pathogenic:2

May 27, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Hemizygote Missense variant c.337C>T in Exon 3 of the AVPR2 gene that results in the amino acid substitution p.Arg113Trp was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 10840). This variant was reported among the patients for nephrogenic diabetes insipidus (Sonia Sharma et al., 2019). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

not provided

Pathogenic:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 113 of the AVPR2 protein (p.Arg113Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with X-linked recessive nephrogenic diabetes insipidus (PMID: 8104196, 10770218, 29594432, 34101133). ClinVar contains an entry for this variant (Variation ID: 10840). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 7984150). This variant disrupts the p.Arg113 amino acid residue in AVPR2. Other variant(s) that disrupt this residue have been observed in individuals with AVPR2-related conditions (PMID: 33009446; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;D;.;D;.

FATHMM_MKL

Benign

0.64

LIST_S2

Pathogenic

0.98

.;.;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

3.4

M;M;.;M;M

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.8

.;D;D;D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.73, 0.73, 0.69

MutPred

0.93

Gain of catalytic residue at L111 (P = 0.0031);Gain of catalytic residue at L111 (P = 0.0031);Gain of catalytic residue at L111 (P = 0.0031);Gain of catalytic residue at L111 (P = 0.0031);Gain of catalytic residue at L111 (P = 0.0031);

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

3.0

Varity_R

0.97

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over