rs104894756

Positions:

• chrX-153905916-G-A
• chrX-153905916-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000054.7(AVPR2):​c.410G>A​(p.Arg137His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,335 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.03

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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, 3 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 id is 10854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-153905916-G-A is Pathogenic according to our data. Variant chrX-153905916-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153905916-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVPR2	NM_000054.7	c.410G>A	p.Arg137His	missense_variant	3/4	ENST00000646375.2
AVPR2	NM_001146151.3	c.410G>A	p.Arg137His	missense_variant	3/3
AVPR2	NR_027419.2	n.466-103G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVPR2	ENST00000646375.2	c.410G>A	p.Arg137His	missense_variant	3/4		NM_000054.7	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD3 exomes AF: 0.00000567 AC: 1 AN: 176496 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089335 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 360545

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 137 of the AVPR2 protein (p.Arg137His). This variant is present in population databases (rs104894756, gnomAD 0.001%). This missense change has been observed in individuals with nephrogenic diabetes insipidus (PMID: 8104196, 9711877, 10820168). ClinVar contains an entry for this variant (Variation ID: 10849). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AVPR2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AVPR2 function (PMID: 9711877, 27355191). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20159941, 10644689, 27649563, 22654789, 11920339, 19179480, 9826914, 7920187, 27355191, 15872203, 16319185, 11134505, 15166253, 9711877, 34020960, 8514744, 8104196, 21183406, 16845277, 10373137, 24030030, 9402099, 10820168, 9452109, 17020465, 8037205) -

Diabetes insipidus, nephrogenic, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 05, 2005

- -

Nephrogenic syndrome of inappropriate antidiuresis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 05, 2005

- -

Nephrogenic diabetes insipidus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 31, 2022

Variant summary: AVPR2 c.410G>A (p.Arg137His) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-06 in 176496 control chromosomes. c.410G>A has been reported in the literature in multiple individuals affected with Nephrogenic Diabetes Insipidus (example, Shoji_1998, Bichet_1993, Bichet_1994, Carroll_2006, Arthus_2000, Ashton_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in the mutant receptor showing normal binding properties, but unable to stimulate the GS/adenylyl cyclase system (Barak_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;D;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;.;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.0	.;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, 0.97
MutPred		0.98		Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs104894756; hg19: chrX-153171370;