Genetic Variant NM_000486.6:c.389C>T (chr12-49954183-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000486.6(AQP2):c.389C>T(p.Ala130Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,162 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. A130A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AQP2
NM_000486.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.35

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 12-49954183-C-T is Pathogenic according to our data. Variant chr12-49954183-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3574913.Status of the report is criteria_provided_single_submitter, 1 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.389C>T	p.Ala130Val	missense	Exon 2 of 4	NP_000477.1	P41181
AQP5-AS1	NR_110590.1		n.422G>A		non_coding_transcript_exon	Exon 2 of 3
AQP5-AS1	NR_110591.1		n.118-2095G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AQP2	ENST00000199280.4	TSL:1 MANE Select	c.389C>T	p.Ala130Val	missense	Exon 2 of 4	ENSP00000199280.3	P41181
AQP2	ENST00000550862.1	TSL:5	c.389C>T	p.Ala130Val	missense	Exon 2 of 3	ENSP00000450022.1	F8VPL3
AQP2	ENST00000551526.5	TSL:5	n.389C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

242292

AF XY:

0.0000152

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1448162

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

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:

40976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4850

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Diabetes insipidus, nephrogenic, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.7

PhyloP100

3.3

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.73

MutPred

0.84

Loss of disorder (P = 0.1124)

MVP

0.99

MPC

1.4

ClinPred

0.97

GERP RS

3.7

Varity_R

0.75

gMVP

0.89

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over