rs104894752

Variant names:

• chrX-153906345-A-G
• rs104894752
• NM_000054.7:c.839A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000054.7(AVPR2):​c.839A>G​(p.Tyr280Cys) 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: 25)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.38

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 10 ACMG points.

• PM1: In a transmembrane_region Helical; Name=6 (size 21) in uniprot entity V2R_HUMAN there are 9 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, 0.944
• PP5: Variant X-153906345-A-G is Pathogenic according to our data. Variant chrX-153906345-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.839A>G	p.Tyr280Cys	missense_variant	Exon 3 of 4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.839A>G	p.Tyr280Cys	missense_variant	Exon 3 of 3		NP_001139623.1
AVPR2	NR_027419.2	n.792A>G		non_coding_transcript_exon_variant	Exon 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.839A>G	p.Tyr280Cys	missense_variant	Exon 3 of 4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+2725T>C		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Diabetes insipidus, nephrogenic, X-linked Pathogenic:1

Aug 30, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

May 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects AVPR2 function (PMID: 9027323, 10644689, 19587238). For these reasons, this variant has been classified as Pathogenic. 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. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 280 of the AVPR2 protein (p.Tyr280Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nephrogenic diabetes insipidus (PMID: 7987330, 8078903, 34101133). ClinVar contains an entry for this variant (Variation ID: 10843). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.0	M;M;M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.0	.;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.016	.;D;D;D
Sift4G	Uncertain	0.011	.;D;D;D
Polyphen		0.89	P;P;P;P
Vest4		0.53, 0.46
MutPred		0.90		Loss of MoRF binding (P = 0.094);Loss of MoRF binding (P = 0.094);Loss of MoRF binding (P = 0.094);Loss of MoRF binding (P = 0.094);
MVP		1.0
MPC		1.0
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.94
gMVP		0.98

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: rs104894752; hg19: chrX-153171799;