chr12-49951041-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000486.6(AQP2):c.211G>A(p.Val71Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
AQP2
NM_000486.6 missense
NM_000486.6 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 6.88
Genes affected
AQP2 (HGNC:634): (aquaporin 2) This gene encodes a water channel protein located in the kidney collecting tubule. It belongs to the MIP/aquaporin family, some members of which are clustered together on chromosome 12q13. Mutations in this gene have been linked to autosomal dominant and recessive forms of nephrogenic diabetes insipidus. [provided by RefSeq, Oct 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a chain Aquaporin-2 (size 270) in uniprot entity AQP2_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_000486.6
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 12-49951041-G-A is Pathogenic according to our data. Variant chr12-49951041-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 446860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49951041-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AQP2 | NM_000486.6 | c.211G>A | p.Val71Met | missense_variant | 1/4 | ENST00000199280.4 | NP_000477.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AQP2 | ENST00000199280.4 | c.211G>A | p.Val71Met | missense_variant | 1/4 | 1 | NM_000486.6 | ENSP00000199280 | P1 | |
AQP2 | ENST00000550862.1 | c.211G>A | p.Val71Met | missense_variant | 1/3 | 5 | ENSP00000450022 | |||
AQP2 | ENST00000551526.5 | c.211G>A | p.Val71Met | missense_variant, NMD_transcript_variant | 1/6 | 5 | ENSP00000447148 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
2
AN:
152250
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250590Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135654
GnomAD3 exomes
AF:
AC:
2
AN:
250590
Hom.:
AF XY:
AC XY:
1
AN XY:
135654
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461526Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727086
GnomAD4 exome
AF:
AC:
17
AN:
1461526
Hom.:
Cov.:
31
AF XY:
AC XY:
6
AN XY:
727086
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74378
GnomAD4 genome
AF:
AC:
2
AN:
152250
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74378
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 25, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 16, 2023 | Experimental studies have shown that this missense change affects AQP2 function (PMID: 12191971, 20711567). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AQP2 protein function. ClinVar contains an entry for this variant (Variation ID: 446860). This missense change has been observed in individuals with autosomal recessive diabetes insipidus (PMID: 12191971, 19147915, 26069764). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs149659001, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 71 of the AQP2 protein (p.Val71Met). - |
Diabetes insipidus, nephrogenic, autosomal Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 29, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of glycosylation at T72 (P = 0.2903);Gain of glycosylation at T72 (P = 0.2903);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at