rs5200

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000054.7(AVPR2):c.440C>T(p.Ala147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,203,388 control chromosomes in the GnomAD database, including 59 homozygotes. There are 919 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 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. A147A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 32 hom., 454 hem., cov: 26)

Exomes 𝑓: 0.0016 ( 27 hom. 465 hem. )

Consequence

AVPR2
NM_000054.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.55

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), Ambry Genetics, Orphanet
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045301914).

BP6

Variant X-153905946-C-T is Benign according to our data. Variant chrX-153905946-C-T is described in ClinVar as Benign. ClinVar VariationId is 254774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000054.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AVPR2	NM_000054.7	MANE Select	c.440C>T	p.Ala147Val	missense	Exon 3 of 4	NP_000045.1	P30518-1
AVPR2	NM_001146151.3		c.440C>T	p.Ala147Val	missense	Exon 3 of 3	NP_001139623.1	P30518-2
AVPR2	NR_027419.2		n.466-73C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AVPR2	ENST00000646375.2	MANE Select	c.440C>T	p.Ala147Val	missense	Exon 3 of 4	ENSP00000496396.1	P30518-1
AVPR2	ENST00000337474.5	TSL:1	c.440C>T	p.Ala147Val	missense	Exon 2 of 3	ENSP00000338072.5	P30518-1
AVPR2	ENST00000370049.1	TSL:1	c.440C>T	p.Ala147Val	missense	Exon 2 of 2	ENSP00000359066.1	P30518-2

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

1742

AN:

113707

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0525

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00577

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000554

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.0149

GnomAD2 exomes

AF:

0.00502

AC:

888

AN:

176773

AF XY:

0.00338

show subpopulations

Gnomad AFR exome

AF:

0.0578

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00201

GnomAD4 exome

AF:

0.00162

AC:

1761

AN:

1089626

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

465

AN XY:

360584

show subpopulations

African (AFR)

AF:

0.0514

AC:

1357

AN:

26401

American (AMR)

AF:

0.00324

AC:

114

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000397

AC:

AN:

30203

South Asian (SAS)

AF:

0.000111

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32017

Middle Eastern (MID)

AF:

0.00218

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000950

AC:

AN:

842088

Other (OTH)

AF:

0.00397

AC:

183

AN:

46043

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0153

AC:

1743

AN:

113762

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

454

AN XY:

35908

show subpopulations

African (AFR)

AF:

0.0524

AC:

1646

AN:

31398

American (AMR)

AF:

0.00577

AC:

AN:

10925

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2665

East Asian (EAS)

AF:

0.000555

AC:

AN:

3602

South Asian (SAS)

AF:

0.00

AC:

AN:

2854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6426

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53424

Other (OTH)

AF:

0.0147

AC:

AN:

1562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00516

Hom.:

237

Bravo

AF:

0.0178

ESP6500AA

AF:

0.0561

AC:

215

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.00540

AC:

656

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Diabetes insipidus, nephrogenic, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.2

PhyloP100

2.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.058

Sift4G

Benign

0.090

Polyphen

0.76

Vest4

0.094

MVP

0.99

MPC

0.96

ClinPred

0.012

GERP RS

3.5

Varity_R

0.25

gMVP

0.94

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over