rs199422215

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000486.6(AQP2):​c.647C>T​(p.Ser216Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 34)

Consequence

AQP2
NM_000486.6 missense

Scores

9
8
2

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 4.13
Variant links:
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]
AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AQP2NM_000486.6 linkc.647C>T p.Ser216Phe missense_variant 4/4 ENST00000199280.4 NP_000477.1 P41181
AQP5-AS1NR_110590.1 linkn.257-1091G>A intron_variant
AQP5-AS1NR_110591.1 linkn.118-3351G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AQP2ENST00000199280.4 linkc.647C>T p.Ser216Phe missense_variant 4/41 NM_000486.6 ENSP00000199280.3 P41181

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
64
GnomAD4 genome
Cov.:
34

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

not provided Other:1
not provided, no classification providedliterature onlyClinVar Staff, National Center for Biotechnology Information (NCBI)-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Uncertain
2.5
M
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.70
MutPred
0.93
Gain of helix (P = 0.2294);
MVP
0.95
MPC
1.5
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.97
gMVP
0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199422215; hg19: chr12-50349222; API