NM_000054.7:c.410G>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000054.7(AVPR2):c.410G>T(p.Arg137Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

AVPR2
NM_000054.7 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.03

Publications

60 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: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000054.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-153905915-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant X-153905916-G-T is Pathogenic according to our data. Variant chrX-153905916-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10855.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7 link	c.410G>T	p.Arg137Leu	missense_variant	Exon 3 of 4	ENST00000646375.2	NP_000045.1	P30518-1
AVPR2	NM_001146151.3 link	c.410G>T	p.Arg137Leu	missense_variant	Exon 3 of 3		NP_001139623.1	P30518-2
AVPR2	NR_027419.2 link	n.466-103G>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2 link	c.410G>T	p.Arg137Leu	missense_variant	Exon 3 of 4		NM_000054.7	ENSP00000496396.1		P30518-1
ENSG00000284987	ENST00000646191.1 link	n.96+3154C>A		intron_variant	Intron 1 of 4			ENSP00000493873.1		A0A2R8Y4P6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1089335

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360545

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31743

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842075

Other (OTH)

AF:

0.00

AC:

AN:

46039

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Nephrogenic syndrome of inappropriate antidiuresis

Pathogenic:1

May 05, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.81

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D;.;D;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

.;.;D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;.;H;H

PhyloP100

8.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.0

.;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, 0.99

MutPred

0.98

Loss of MoRF binding (P = 0.0577);Loss of MoRF binding (P = 0.0577);Loss of MoRF binding (P = 0.0577);Loss of MoRF binding (P = 0.0577);Loss of MoRF binding (P = 0.0577);

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

3.9

Varity_R

0.99

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over