rs5200

chrX-153905946-C-T

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.440C>T(p.Ala147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,203,388 control chromosomes in the GnomAD database, including 59 homozygotes. There are 919 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 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. A147A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (32 hom., 454 hem., cov: 26)
  • Exomes 𝑓: 0.0016 (27 hom. 465 hem.)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.55

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=0.0045301914).
• BP6: Variant X-153905946-C-T is Benign according to our data. Variant chrX-153905946-C-T is described in ClinVar as [Benign]. Clinvar id is 254774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AVPR2	NM_000054.7	c.440C>T	p.Ala147Val	missense_variant	3/4	ENST00000646375.2
AVPR2	NM_001146151.3	c.440C>T	p.Ala147Val	missense_variant	3/3
AVPR2	NR_027419.2	n.466-73C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AVPR2	ENST00000646375.2	c.440C>T	p.Ala147Val	missense_variant	3/4		NM_000054.7	P1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 1742 AN: 113707 Hom.: 32 Cov.: 26 AF XY: 0.0127 AC XY: 457 AN XY: 35843

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000554

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.00502 AC: 888 AN: 176773 Hom.: 13 AF XY: 0.00338 AC XY: 221 AN XY: 65321

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00162 AC: 1761 AN: 1089626 Hom.: 27 Cov.: 36 AF XY: 0.00129 AC XY: 465 AN XY: 360584

Gnomad4 AFR exome AF: 0.0514

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000397

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000950

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.0153 AC: 1743 AN: 113762 Hom.: 32 Cov.: 26 AF XY: 0.0126 AC XY: 454 AN XY: 35908

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.00577

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000555

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00191 Hom.: 82

Bravo AF: 0.0178

ESP6500AA AF: 0.0561 AC: 215

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00540 AC: 656

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Diabetes insipidus, nephrogenic, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;T;.
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.0045	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.2	L;L;.;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
Polyphen		0.76	P;P;.;P;P
Vest4		0.094, 0.095, 0.11
MVP		0.99
MPC		0.96
ClinPred		0.012	T
GERP RS		3.5
Varity_R		0.25
gMVP		0.94

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: rs5200; hg19: chrX-153171400;