Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000486.6(AQP2):c.377C>A(p.Thr126Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,276 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T126M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AQP2
NM_000486.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

Publications

36 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 links:

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

AQP5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-49954171-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000486.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AQP2	NM_000486.6	MANE Select	c.377C>A	p.Thr126Lys	missense	Exon 2 of 4	NP_000477.1
AQP5-AS1	NR_110590.1		n.434G>T		non_coding_transcript_exon	Exon 2 of 3
AQP5-AS1	NR_110591.1		n.118-2083G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AQP2	ENST00000199280.4	TSL:1 MANE Select	c.377C>A	p.Thr126Lys	missense	Exon 2 of 4	ENSP00000199280.3
AQP2	ENST00000550862.1	TSL:5	c.377C>A	p.Thr126Lys	missense	Exon 2 of 3	ENSP00000450022.1
AQP2	ENST00000551526.5	TSL:5	n.377C>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000447148.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000413

AC:

AN:

241842

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720440

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4652

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.3

PhyloP100

1.7

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.64

Sift

Uncertain

0.018

Sift4G

Uncertain

0.042

Polyphen

0.80

Vest4

0.71

MutPred

0.60

Gain of ubiquitination at T126 (P = 0.0267)

MVP

0.97

MPC

0.95

ClinPred

0.92

GERP RS

4.6

Varity_R

0.53

gMVP

0.89

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-49954171-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over