NM_000486.6:c.374C>T

Variant names:

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.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 1,599,382 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

AQP2
NM_000486.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.94

Publications

19 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: 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, 3 uncertain in NM_000486.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 12-49954168-C-T is Pathogenic according to our data. Variant chr12-49954168-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	UniProt
AQP2	NM_000486.6	MANE Select	c.374C>T	p.Thr125Met	missense	Exon 2 of 4	NP_000477.1	P41181
AQP5-AS1	NR_110590.1		n.437G>A		non_coding_transcript_exon	Exon 2 of 3
AQP5-AS1	NR_110591.1		n.118-2080G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AQP2	ENST00000199280.4	TSL:1 MANE Select	c.374C>T	p.Thr125Met	missense	Exon 2 of 4	ENSP00000199280.3	P41181
AQP2	ENST00000550862.1	TSL:5	c.374C>T	p.Thr125Met	missense	Exon 2 of 3	ENSP00000450022.1	F8VPL3
AQP2	ENST00000551526.5	TSL:5	n.374C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000827

AC:

AN:

241708

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00000691

AC:

AN:

1447050

Hom.:

Cov.:

AF XY:

0.00000972

AC XY:

AN XY:

720318

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4596

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111916

Other (OTH)

AF:

0.00

AC:

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.0000263

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Diabetes insipidus, nephrogenic, autosomal (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.0085

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.016

MutationAssessor

Benign

1.4

PhyloP100

1.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.62

Sift

Benign

0.073

Sift4G

Benign

0.093

Polyphen

0.99

Vest4

0.67

MutPred

0.82

Loss of disorder (P = 0.0887)

MVP

0.95

MPC

1.4

ClinPred

0.37

GERP RS

4.6

Varity_R

0.20

gMVP

0.54

Mutation Taster

=77/23

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over