rs5202

Positions:

• chrX-153906605-C-T

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.993C>T​(p.Ser331Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,200,046 control chromosomes in the GnomAD database, including 1,149 homozygotes. There are 12,728 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (420 hom., 2304 hem., cov: 24)
  • Exomes 𝑓: 0.030 (729 hom. 10424 hem.)
• Consequence: AVPR2 NM_000054.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.959

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]

ENSG00000284987 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020931363).
• BP6: Variant X-153906605-C-T is Benign according to our data. Variant chrX-153906605-C-T is described in ClinVar as [Benign]. Clinvar id is 254776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153906605-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.959 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.993C>T	p.Ser331Ser	synonymous_variant	4/4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.*169C>T		3_prime_UTR_variant	3/3		NP_001139623.1
AVPR2	NR_027419.2	n.946C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.993C>T	p.Ser331Ser	synonymous_variant	4/4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+2465G>A		intron_variant				ENSP00000493873.1

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 7872 AN: 112495 Hom.: 419 Cov.: 24 AF XY: 0.0660 AC XY: 2289 AN XY: 34669

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.0536

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0570

GnomAD3 exomes AF: 0.0492 AC: 8529 AN: 173445 Hom.: 327 AF XY: 0.0428 AC XY: 2535 AN XY: 59247

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.0287

Gnomad SAS exome AF: 0.0513

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0441

GnomAD4 exome AF: 0.0297 AC: 32284 AN: 1087498 Hom.: 729 Cov.: 33 AF XY: 0.0294 AC XY: 10424 AN XY: 354952

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.0418

Gnomad4 SAS exome AF: 0.0552

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0354

GnomAD4 genome AF: 0.0701 AC: 7888 AN: 112548 Hom.: 420 Cov.: 24 AF XY: 0.0663 AC XY: 2304 AN XY: 34732

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.0652

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.0265

Gnomad4 SAS AF: 0.0538

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0562

Alfa AF: 0.0397 Hom.: 325

Bravo AF: 0.0795

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0156 AC: 45

ESP6500AA AF: 0.181 AC: 693

ESP6500EA AF: 0.0196 AC: 132

ExAC AF: 0.0479 AC: 5820

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

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	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:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.068
DANN	Benign	0.86
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.24
Sift	Benign	0.18	T
Sift4G	Benign	0.20	T
ClinPred		0.0020	T
GERP RS		-0.047

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: rs5202; hg19: chrX-153172059;