NM_000054.7:c.69C>G

Variant names:

• chrX-153905575-C-G
• rs377144623
• NM_000054.7:c.69C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000054.7(AVPR2):​c.69C>G​(p.Ser23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,089,310 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10257885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.69C>G	p.Ser23Arg	missense_variant	Exon 3 of 4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.69C>G	p.Ser23Arg	missense_variant	Exon 3 of 3		NP_001139623.1
AVPR2	NR_027419.2	n.465+405C>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.69C>G	p.Ser23Arg	missense_variant	Exon 3 of 4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+3495G>C		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1089310 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 357102

African (AFR) AF: 0.00 AC: 0 AN: 26217

American (AMR) AF: 0.00 AC: 0 AN: 34247

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19201

East Asian (EAS) AF: 0.00 AC: 0 AN: 29686

South Asian (SAS) AF: 0.00 AC: 0 AN: 53025

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39123

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3940

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 838195

Other (OTH) AF: 0.00 AC: 0 AN: 45676

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;T;.;T;.
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.46	.;.;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	M;M;.;M;M
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	.;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.18	.;T;D;T;T
Sift4G	Benign	0.40	.;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.18, 0.16
MutPred		0.21		Loss of phosphorylation at S23 (P = 0.0287);Loss of phosphorylation at S23 (P = 0.0287);Loss of phosphorylation at S23 (P = 0.0287);Loss of phosphorylation at S23 (P = 0.0287);Loss of phosphorylation at S23 (P = 0.0287);
MVP		0.91
MPC		0.72
ClinPred		0.065	T
GERP RS		3.1
PromoterAI		-0.026	Neutral
Varity_R		0.14
gMVP		0.82
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377144623; hg19: chrX-153171029;