X-153905551-TCTGCCCAGC-TCTGCCCAGCCTGCCCAGC
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM4
The NM_000054.7(AVPR2):c.55_63dupCTGCCCAGC(p.Leu19_Ser21dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,675 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 26)
Consequence
AVPR2
NM_000054.7 conservative_inframe_insertion
NM_000054.7 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.377
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-linkedInheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
- nephrogenic syndrome of inappropriate antidiuresisInheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
- nephrogenic diabetes insipidusInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
PM1
In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity V2R_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000054.7.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| AVPR2 | NM_000054.7 | c.55_63dupCTGCCCAGC | p.Leu19_Ser21dup | conservative_inframe_insertion | Exon 3 of 4 | ENST00000646375.2 | NP_000045.1 | |
| AVPR2 | NM_001146151.3 | c.55_63dupCTGCCCAGC | p.Leu19_Ser21dup | conservative_inframe_insertion | Exon 3 of 3 | NP_001139623.1 | ||
| AVPR2 | NR_027419.2 | n.465+391_465+399dupCTGCCCAGC | intron_variant | Intron 2 of 3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| AVPR2 | ENST00000646375.2 | c.55_63dupCTGCCCAGC | p.Leu19_Ser21dup | conservative_inframe_insertion | Exon 3 of 4 | NM_000054.7 | ENSP00000496396.1 | |||
| ENSG00000284987 | ENST00000646191.1 | n.96+3510_96+3518dupGCTGGGCAG | intron_variant | Intron 1 of 4 | ENSP00000493873.1 |
Frequencies
GnomAD3 genomes 0.0000178 AC: 2AN: 112675Hom.: 0 Cov.: 26 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
112675
Hom.:
Cov.:
26
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad ASJ
AF:
Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome 0.0000178 AC: 2AN: 112675Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 34841 show subpopulations
GnomAD4 genome
AF:
AC:
2
AN:
112675
Hom.:
Cov.:
26
AF XY:
AC XY:
0
AN XY:
34841
show subpopulations
African (AFR)
AF:
AC:
2
AN:
31049
American (AMR)
AF:
AC:
0
AN:
10823
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
2663
East Asian (EAS)
AF:
AC:
0
AN:
3549
South Asian (SAS)
AF:
AC:
0
AN:
2762
European-Finnish (FIN)
AF:
AC:
0
AN:
6271
Middle Eastern (MID)
AF:
AC:
0
AN:
239
European-Non Finnish (NFE)
AF:
AC:
0
AN:
53114
Other (OTH)
AF:
AC:
0
AN:
1525
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Diabetes insipidus, nephrogenic, X-linked;C1845202:Nephrogenic syndrome of inappropriate antidiuresis Uncertain:1
May 30, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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