rs2071126

Positions:

• chrX-153905541-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.11

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 Benign. Variant got -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 id is 254773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153905541-G-A is described in Lovd as [Benign]. Variant chrX-153905541-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVPR2	NM_000054.7	c.35G>A	p.Gly12Glu	missense_variant	3/4	ENST00000646375.2
AVPR2	NM_001146151.3	c.35G>A	p.Gly12Glu	missense_variant	3/3
AVPR2	NR_027419.2	n.465+371G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVPR2	ENST00000646375.2	c.35G>A	p.Gly12Glu	missense_variant	3/4		NM_000054.7	P1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 2726 AN: 112534 Hom.: 39 Cov.: 26 AF XY: 0.0247 AC XY: 856 AN XY: 34718

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

GnomAD3 exomes AF: 0.0381 AC: 5264 AN: 138128 Hom.: 129 AF XY: 0.0377 AC XY: 1626 AN XY: 43142

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 SAS exome AF: 0.0568

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.: 35 AF XY: 0.0246 AC XY: 8646 AN XY: 351270

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.0871

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.0443

Gnomad4 SAS exome AF: 0.0583

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0230

GnomAD4 genome AF: 0.0242 AC: 2723 AN: 112586 Hom.: 38 Cov.: 26 AF XY: 0.0247 AC XY: 858 AN XY: 34780

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.0501

Gnomad4 ASJ AF: 0.0169

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.0553

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0272

Alfa AF: 0.0216 Hom.: 252

Bravo AF: 0.0266

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0145 AC: 42

ESP6500AA AF: 0.0226 AC: 81

ESP6500EA AF: 0.0167 AC: 107

ExAC AF: 0.0311 AC: 3667

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 10526945, 27884173, 20403097, 9027323, 7987330, 22995991, 22644838) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Diabetes insipidus, nephrogenic, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.7
DANN	Benign	0.68
DEOGEN2	Benign	0.40	T;T;.;T;.
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.71	.;.;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.45	.;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.72	.;T;D;T;T
Sift4G	Benign	0.62	.;T;T;T;T
Polyphen		0.0040	B;B;.;B;B
Vest4		0.037, 0.039, 0.038
MPC		0.71
ClinPred		0.0029	T
GERP RS		0.23
Varity_R		0.057
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs2071126; hg19: chrX-153170995; COSMIC: COSV61685746; COSMIC: COSV61685746;