rs104894756

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000054.7(AVPR2):c.410G>A(p.Arg137His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,335 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

AVPR2
NM_000054.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.03

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 14 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-153905916-G-A is Pathogenic according to our data. Variant chrX-153905916-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153905916-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AVPR2	NM_000054.7 link	c.410G>A	p.Arg137His	missense_variant	3/4	ENST00000646375.2	NP_000045.1	P30518-1
AVPR2	NM_001146151.3 link	c.410G>A	p.Arg137His	missense_variant	3/3		NP_001139623.1	P30518-2
AVPR2	NR_027419.2 link	n.466-103G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2 link	c.410G>A	p.Arg137His	missense_variant	3/4		NM_000054.7	ENSP00000496396.1		P30518-1
ENSG00000284987	ENST00000646191.1 link	n.96+3154C>T		intron_variant				ENSP00000493873.1		A0A2R8Y4P6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000567

AC:

AN:

176496

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65290

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:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.18e-7

AC:

AN:

1089335

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360545

show subpopulations

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 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: 20159941, 10644689, 27649563, 22654789, 11920339, 19179480, 9826914, 7920187, 27355191, 15872203, 16319185, 11134505, 15166253, 9711877, 34020960, 8514744, 8104196, 21183406, 16845277, 10373137, 24030030, 9402099, 10820168, 9452109, 17020465, 8037205) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 137 of the AVPR2 protein (p.Arg137His). This variant is present in population databases (rs104894756, gnomAD 0.001%). This missense change has been observed in individuals with nephrogenic diabetes insipidus (PMID: 8104196, 9711877, 10820168). ClinVar contains an entry for this variant (Variation ID: 10849). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AVPR2 function (PMID: 9711877, 27355191). For these reasons, this variant has been classified as Pathogenic. -

Diabetes insipidus, nephrogenic, X-linked

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 05, 2005

- -

Nephrogenic syndrome of inappropriate antidiuresis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 05, 2005

- -

Nephrogenic diabetes insipidus

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 31, 2022

Variant summary: AVPR2 c.410G>A (p.Arg137His) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-06 in 176496 control chromosomes. c.410G>A has been reported in the literature in multiple individuals affected with Nephrogenic Diabetes Insipidus (example, Shoji_1998, Bichet_1993, Bichet_1994, Carroll_2006, Arthus_2000, Ashton_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in the mutant receptor showing normal binding properties, but unable to stimulate the GS/adenylyl cyclase system (Barak_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.81

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;D;.;D;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

.;.;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;.;H;H

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.0

.;D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.99, 0.97

MutPred

0.98

Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

3.9

Varity_R

0.98

gMVP

0.99

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