rs2071126

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.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. 15/20 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. 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:9

Conservation

PhyloP100: 1.11

Publications

13 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 -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 VariationId is 254773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0844 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
AVPR2	NM_000054.7	MANE Select	c.35G>A	p.Gly12Glu	missense	Exon 3 of 4	NP_000045.1
AVPR2	NM_001146151.3		c.35G>A	p.Gly12Glu	missense	Exon 3 of 3	NP_001139623.1
AVPR2	NR_027419.2		n.465+371G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AVPR2	ENST00000646375.2	MANE Select	c.35G>A	p.Gly12Glu	missense	Exon 3 of 4	ENSP00000496396.1
AVPR2	ENST00000337474.5	TSL:1	c.35G>A	p.Gly12Glu	missense	Exon 2 of 3	ENSP00000338072.5
AVPR2	ENST00000370049.1	TSL:1	c.35G>A	p.Gly12Glu	missense	Exon 2 of 2	ENSP00000359066.1

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

2726

AN:

112534

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0381

AC:

5264

AN:

138128

AF XY:

0.0377

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 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

African (AFR)

AF:

0.0213

AC:

551

AN:

25861

American (AMR)

AF:

0.0871

AC:

2834

AN:

32537

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

328

AN:

18989

East Asian (EAS)

AF:

0.0443

AC:

1280

AN:

28917

South Asian (SAS)

AF:

0.0583

AC:

3032

AN:

51972

European-Finnish (FIN)

AF:

0.0200

AC:

764

AN:

38283

Middle Eastern (MID)

AF:

0.0643

AC:

232

AN:

3609

European-Non Finnish (NFE)

AF:

0.0187

AC:

15541

AN:

832052

Other (OTH)

AF:

0.0230

AC:

1039

AN:

45202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1022

2044

3065

4087

5109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

642

1284

1926

2568

3210

<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:

0.0242

AC:

2723

AN:

112586

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

858

AN XY:

34780

show subpopulations

African (AFR)

AF:

0.0225

AC:

698

AN:

31084

American (AMR)

AF:

0.0501

AC:

541

AN:

10790

Ashkenazi Jewish (ASJ)

AF:

0.0169

AC:

AN:

2657

East Asian (EAS)

AF:

0.0274

AC:

AN:

3541

South Asian (SAS)

AF:

0.0553

AC:

152

AN:

2747

European-Finnish (FIN)

AF:

0.0203

AC:

126

AN:

6221

Middle Eastern (MID)

AF:

0.0324

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0191

AC:

1015

AN:

53108

Other (OTH)

AF:

0.0272

AC:

AN:

1542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0216

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Diabetes insipidus, nephrogenic, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.7

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.40

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.45

REVEL

Benign

0.048

Sift

Benign

0.72

Sift4G

Benign

0.62

Polyphen

0.0040

Vest4

0.037

MPC

0.71

ClinPred

0.0029

GERP RS

0.23

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.057

gMVP

0.73

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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