rs28935496

Positions:

• chrX-153905843-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.135

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]

ENSG00000284987 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.337C>T	p.Arg113Trp	missense_variant	3/4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.337C>T	p.Arg113Trp	missense_variant	3/3		NP_001139623.1
AVPR2	NR_027419.2	n.466-176C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.337C>T	p.Arg113Trp	missense_variant	3/4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+3227G>A		intron_variant				ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD3 exomes AF: 0.00000563 AC: 1 AN: 177487 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65413

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: 0 AN: 1091444 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 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.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diabetes insipidus, nephrogenic, X-linked Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 27, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2023

For these reasons, this variant has been classified as Pathogenic. 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; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects AVPR2 function (PMID: 7984150). 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. ClinVar contains an entry for this variant (Variation ID: 10840). This missense change has been observed in individuals with X-linked recessive nephrogenic diabetes insipidus (PMID: 8104196, 10770218, 29594432, 34101133). 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 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;D;.
FATHMM_MKL	Benign	0.64	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.4	M;M;.;M;M
PrimateAI	Uncertain	0.79	T
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	D
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

Other links and lift over

dbSNP: rs28935496; hg19: chrX-153171297; COSMIC: COSV61686589; COSMIC: COSV61686589;