rs5202

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000054.7(AVPR2):c.993C>T(p.Ser331Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,200,046 control chromosomes in the GnomAD database, including 1,149 homozygotes. There are 12,728 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.070 ( 420 hom., 2304 hem., cov: 24)

Exomes 𝑓: 0.030 ( 729 hom. 10424 hem. )

Consequence

AVPR2
NM_000054.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.959

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

diabetes insipidus, nephrogenic, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
nephrogenic syndrome of inappropriate antidiuresis
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
nephrogenic diabetes insipidus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

AVPR2 links:

ENSG00000284987 (HGNC:):

ENSG00000284987 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020931363).

BP6

Variant X-153906605-C-T is Benign according to our data. Variant chrX-153906605-C-T is described in ClinVar as [Benign]. Clinvar id is 254776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.959 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7 link	c.993C>T	p.Ser331Ser	synonymous_variant	Exon 4 of 4	ENST00000646375.2	NP_000045.1	P30518-1
AVPR2	NR_027419.2 link	n.946C>T		non_coding_transcript_exon_variant	Exon 4 of 4
AVPR2	NM_001146151.3 link	c.*169C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001139623.1	P30518-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2 link	c.993C>T	p.Ser331Ser	synonymous_variant	Exon 4 of 4		NM_000054.7	ENSP00000496396.1		P30518-1
ENSG00000284987	ENST00000646191.1 link	n.96+2465G>A		intron_variant	Intron 1 of 4			ENSP00000493873.1		A0A2R8Y4P6

Frequencies

GnomAD3 genomes

AF:

0.0700

AC:

7872

AN:

112495

Hom.:

419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.0655

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.0267

Gnomad SAS

AF:

0.0536

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.0420

Gnomad NFE

AF:

0.0205

Gnomad OTH

AF:

0.0570

GnomAD2 exomes

AF:

0.0492

AC:

8529

AN:

173445

AF XY:

0.0428

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.0287

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.0203

Gnomad OTH exome

AF:

0.0441

GnomAD4 exome

AF:

0.0297

AC:

32284

AN:

1087498

Hom.:

729

Cov.:

AF XY:

0.0294

AC XY:

10424

AN XY:

354952

show subpopulations

African (AFR)

AF:

0.185

AC:

4858

AN:

26220

American (AMR)

AF:

0.0977

AC:

3368

AN:

34487

Ashkenazi Jewish (ASJ)

AF:

0.0168

AC:

316

AN:

18763

East Asian (EAS)

AF:

0.0418

AC:

1256

AN:

30035

South Asian (SAS)

AF:

0.0552

AC:

2901

AN:

52594

European-Finnish (FIN)

AF:

0.0203

AC:

818

AN:

40231

Middle Eastern (MID)

AF:

0.0618

AC:

252

AN:

4078

European-Non Finnish (NFE)

AF:

0.0202

AC:

16902

AN:

835500

Other (OTH)

AF:

0.0354

AC:

1613

AN:

45590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1339

2678

4017

5356

6695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

772

1544

2316

3088

3860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0701

AC:

7888

AN:

112548

Hom.:

420

Cov.:

AF XY:

0.0663

AC XY:

2304

AN XY:

34732

show subpopulations

African (AFR)

AF:

0.180

AC:

5568

AN:

30901

American (AMR)

AF:

0.0652

AC:

700

AN:

10730

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

2657

East Asian (EAS)

AF:

0.0265

AC:

AN:

3587

South Asian (SAS)

AF:

0.0538

AC:

150

AN:

2788

European-Finnish (FIN)

AF:

0.0207

AC:

129

AN:

6224

Middle Eastern (MID)

AF:

0.0323

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0205

AC:

1092

AN:

53234

Other (OTH)

AF:

0.0562

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

243

487

730

974

1217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0397

Hom.:

325

Bravo

AF:

0.0795

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.181

AC:

693

ESP6500EA

AF:

0.0196

AC:

132

ExAC

AF:

0.0479

AC:

5820

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 08, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diabetes insipidus, nephrogenic, X-linked

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

0.068

(source)

DANN

Benign

0.86

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.0

PhyloP100

-0.96

PROVEAN

Benign

-0.25

REVEL

Benign

0.24

Sift

Benign

0.18

Sift4G

Benign

0.20

ClinPred

0.0020

GERP RS

-0.047

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over