rs5201

chrX-153906539-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000054.7(AVPR2):c.927A>G(p.Leu309=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,204,137 control chromosomes in the GnomAD database, including 66,424 homozygotes. There are 147,760 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (12623 hom., 17014 hem., cov: 23)
  • Exomes 𝑓: 0.35 (53801 hom. 130746 hem.)
• Consequence: AVPR2 NM_000054.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.37

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3549908E-6).
• BP6: Variant X-153906539-A-G is Benign according to our data. Variant chrX-153906539-A-G is described in ClinVar as [Benign]. Clinvar id is 254775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153906539-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVPR2	NM_000054.7	c.927A>G	p.Leu309=	synonymous_variant	4/4	ENST00000646375.2
AVPR2	NM_001146151.3	c.*103A>G		3_prime_UTR_variant	3/3
AVPR2	NR_027419.2	n.880A>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVPR2	ENST00000646375.2	c.927A>G	p.Leu309=	synonymous_variant	4/4		NM_000054.7	P1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 56442 AN: 110772 Hom.: 12615 Cov.: 23 AF XY: 0.513 AC XY: 16956 AN XY: 33032

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.0784

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.485

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.518

GnomAD3 exomes AF: 0.475 AC: 83957 AN: 176633 Hom.: 16385 AF XY: 0.457 AC XY: 28242 AN XY: 61855

Gnomad AFR exome AF: 0.875

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.718

Gnomad SAS exome AF: 0.703

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.355 AC: 387930 AN: 1093309 Hom.: 53801 Cov.: 36 AF XY: 0.364 AC XY: 130746 AN XY: 359545

Gnomad4 AFR exome AF: 0.878

Gnomad4 AMR exome AF: 0.674

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.716

Gnomad4 SAS exome AF: 0.704

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.510 AC: 56508 AN: 110828 Hom.: 12623 Cov.: 23 AF XY: 0.514 AC XY: 17014 AN XY: 33098

Gnomad4 AFR AF: 0.865

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.708

Gnomad4 SAS AF: 0.718

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.525

Alfa AF: 0.364 Hom.: 11399

Bravo AF: 0.546

TwinsUK AF: 0.290 AC: 1077

ALSPAC AF: 0.292 AC: 843

ESP6500AA AF: 0.857 AC: 3287

ESP6500EA AF: 0.300 AC: 2018

ExAC AF: 0.471 AC: 57094

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Diabetes insipidus, nephrogenic, X-linked Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Nephrogenic syndrome of inappropriate antidiuresis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.1
Dann	Benign	0.85
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	4.1e-19	P;P;P
PROVEAN	Pathogenic	-7.5	D
REVEL	Benign	0.26
Sift	Benign	0.23	T
Sift4G	Uncertain	0.042	D
ClinPred		0.038	T
GERP RS		3.4

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: rs5201; hg19: chrX-153171993; COSMIC: COSV61685769; COSMIC: COSV61685769;