rs149659001

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AQP2
NM_000486.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.88

Publications

12 publications found

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]

AQP2 Gene-Disease associations (from GenCC):

diabetes insipidus, nephrogenic, autosomal
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
nephrogenic diabetes insipidus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

AQP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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/Likely_pathogenic. ClinVar VariationId is 446860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP2	NM_000486.6 link	c.211G>A	p.Val71Met	missense_variant	Exon 1 of 4	ENST00000199280.4	NP_000477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AQP2	ENST00000199280.4 link	c.211G>A	p.Val71Met	missense_variant	Exon 1 of 4	1	NM_000486.6	ENSP00000199280.3
AQP2	ENST00000550862.1 link	c.211G>A	p.Val71Met	missense_variant	Exon 1 of 3	5		ENSP00000450022.1
AQP2	ENST00000551526.5 link	n.211G>A		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000447148.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250590

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111958

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal

Pathogenic:4

Oct 29, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.211G>A (p.Val71Met) variant in the AQP2 gene which is located in a mutational hot spot has been reported previously in a homozygous state in individuals affected with nephrogenic diabetes insipidus (NDI) (Bichet et al., 2016). Experimental studies have shown that this missense change affects the AQP2 function (Marr et al., 2002; Lussier et al., 2010). The amino acid Val at position 71 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Val71Met in AQP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with diabetes insipidus, nephrogenic, 2 (MIM#125800). Missense variants have been described with either a dominant negative or loss of function mechanism. Protein truncating variants have a loss of function mechanism, whereas frameshift variants causing an elongation are dominant negative (OMIM, PMID: 12191971, PMID: 26069764, PMID: 11536078). (I) 0108 - This gene is associated with both recessive and dominant disease. Loss of function variants result in recessive disease, whereas dominant negative variants result in dominant disease (PMID: 12191971, PMID: 26069764, PMID: 11536078). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated CII domain (PMID: 26069764). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and observed in multiple homozygous individuals with diabetes insipidus (ClinVar, PMID: 12191971, PMID: 30976394, PMID: 26069764). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Expression of this variant in oocytes showed significantly reduced water permeability and protein mislocalization (PMID: 12191971). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jan 25, 2017

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 446860). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AQP2 function (PMID: 12191971, 20711567). 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. 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

PhyloP100

6.9

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.93

MutPred

0.96

Gain of glycosylation at T72 (P = 0.2903);Gain of glycosylation at T72 (P = 0.2903);

MVP

0.99

MPC

1.4

ClinPred

1.0

GERP RS

4.6

PromoterAI

0.026

Neutral

(source)

Varity_R

0.79

gMVP

0.84

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over