rs1473798821

Variant names:

• chrX-153905163-C-T
• rs1473798821
• NM_000054.7:c.18C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000054.7(AVPR2):​c.18C>T​(p.Thr6Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 112,639 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.000053 (0 hom., 2 hem., cov: 24)
• Consequence: AVPR2 NM_000054.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.567
• Publications: 0 publications found

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]

AVPR2 Gene-Disease associations (from GenCC):

• diabetes insipidus, nephrogenic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nephrogenic syndrome of inappropriate antidiuresis

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• nephrogenic diabetes insipidus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284987 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-153905163-C-T is Benign according to our data. Variant chrX-153905163-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2890168.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.567 with no splicing effect.
• BS2: High AC in GnomAd4 at 6 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.18C>T	p.Thr6Thr	synonymous_variant	Exon 2 of 4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.18C>T	p.Thr6Thr	synonymous_variant	Exon 2 of 3		NP_001139623.1
AVPR2	NR_027419.2	n.458C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.18C>T	p.Thr6Thr	synonymous_variant	Exon 2 of 4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+3907G>A		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes AF: 0.0000533 AC: 6 AN: 112639 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000533 AC: 6 AN: 112639 Hom.: 0 Cov.: 24 AF XY: 0.0000575 AC XY: 2 AN XY: 34795

African (AFR) AF: 0.000194 AC: 6 AN: 31002

American (AMR) AF: 0.00 AC: 0 AN: 10751

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6293

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53214

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.65
PhyloP100		0.57
PromoterAI		-0.033	Neutral

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

Other links and lift over

dbSNP: rs1473798821; hg19: chrX-153170617;