rs193922112

Variant names:

• chrX-153905682-T-C
• rs193922112
• NM_000054.7:c.176T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000054.7(AVPR2):​c.176T>C​(p.Leu59Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,113 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AVPR2 NM_000054.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.77
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-153905682-T-C is Pathogenic according to our data. Variant chrX-153905682-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 35737.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AVPR2	NM_000054.7	c.176T>C	p.Leu59Pro	missense_variant	Exon 3 of 4	ENST00000646375.2	NP_000045.1
AVPR2	NM_001146151.3	c.176T>C	p.Leu59Pro	missense_variant	Exon 3 of 3		NP_001139623.1
AVPR2	NR_027419.2	n.466-337T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AVPR2	ENST00000646375.2	c.176T>C	p.Leu59Pro	missense_variant	Exon 3 of 4		NM_000054.7	ENSP00000496396.1
ENSG00000284987	ENST00000646191.1	n.96+3388A>G		intron_variant	Intron 1 of 4			ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097113 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 362959

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19348

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54115

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841808

Other (OTH) AF: 0.00 AC: 0 AN: 46026

GnomAD4 genome Cov.: 26

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrogenic diabetes insipidus Pathogenic:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;D;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	.;.;T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.5	M;M;.;M;M
PhyloP100		5.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.9	.;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.95, 0.95, 0.94
MutPred		0.94		Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);Gain of disorder (P = 0.059);
MVP		1.0
MPC		1.8
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.99
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs193922112; hg19: chrX-153171136;