rs2071126

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000054.7(AVPR2):c.35G>A(p.Gly12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,190,008 control chromosomes in the GnomAD database, including 371 homozygotes. There are 9,504 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G12G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.024 ( 38 hom., 858 hem., cov: 26)

Exomes 𝑓: 0.024 ( 333 hom. 8646 hem. )

Consequence

AVPR2
NM_000054.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018711984).

BP6

Variant X-153905541-G-A is Benign according to our data. Variant chrX-153905541-G-A is described in ClinVar as [Benign]. Clinvar id is 254773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153905541-G-A is described in Lovd as [Benign]. Variant chrX-153905541-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AVPR2	NM_000054.7 linkuse as main transcript	c.35G>A	p.Gly12Glu	missense_variant	3/4	ENST00000646375.2
AVPR2	NM_001146151.3 linkuse as main transcript	c.35G>A	p.Gly12Glu	missense_variant	3/3
AVPR2	NR_027419.2 linkuse as main transcript	n.465+371G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVPR2	ENST00000646375.2 linkuse as main transcript	c.35G>A	p.Gly12Glu	missense_variant	3/4		NM_000054.7	P1	P30518-1

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

2726

AN:

112534

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

856

AN XY:

34718

show subpopulations

Gnomad AFR

AF:

0.0225

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0504

Gnomad ASJ

AF:

0.0169

Gnomad EAS

AF:

0.0276

Gnomad SAS

AF:

0.0541

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.0276

GnomAD3 exomes

AF:

0.0381

AC:

5264

AN:

138128

Hom.:

129

AF XY:

0.0377

AC XY:

1626

AN XY:

43142

show subpopulations

Gnomad AFR exome

AF:

0.0215

Gnomad AMR exome

AF:

0.0965

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.0294

Gnomad SAS exome

AF:

0.0568

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0393

GnomAD4 exome

AF:

0.0238

AC:

25601

AN:

1077422

Hom.:

333

Cov.:

AF XY:

0.0246

AC XY:

8646

AN XY:

351270

show subpopulations

Gnomad4 AFR exome

AF:

0.0213

Gnomad4 AMR exome

AF:

0.0871

Gnomad4 ASJ exome

AF:

0.0173

Gnomad4 EAS exome

AF:

0.0443

Gnomad4 SAS exome

AF:

0.0583

Gnomad4 FIN exome

AF:

0.0200

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0230

GnomAD4 genome

AF:

0.0242

AC:

2723

AN:

112586

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

858

AN XY:

34780

show subpopulations

Gnomad4 AFR

AF:

0.0225

Gnomad4 AMR

AF:

0.0501

Gnomad4 ASJ

AF:

0.0169

Gnomad4 EAS

AF:

0.0274

Gnomad4 SAS

AF:

0.0553

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.0191

Gnomad4 OTH

AF:

0.0272

Alfa

AF:

0.0216

Hom.:

252

Bravo

AF:

0.0266

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.0226

AC:

ESP6500EA

AF:

0.0167

AC:

107

ExAC

AF:

0.0311

AC:

3667

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 18, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 10526945, 27884173, 20403097, 9027323, 7987330, 22995991, 22644838) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Diabetes insipidus, nephrogenic, X-linked

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.66

Cadd

Benign

6.7

Dann

Benign

0.68

DEOGEN2

Benign

0.40

T;T;.;T;.

FATHMM_MKL

Benign

0.071

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;.;L;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.28

Polyphen

0.0040

B;B;.;B;B

Vest4

0.037, 0.039, 0.038

MPC

0.71

ClinPred

0.0029

GERP RS

0.23

Varity_R

0.057

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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