Genetic Variant AQP2:c.*1684T>C (chr12-49957292-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000486.6(AQP2):c.*1684T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,098 control chromosomes in the GnomAD database, including 10,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10123 hom., cov: 32)

Exomes 𝑓: 0.31 ( 9 hom. )

Consequence

AQP2
NM_000486.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.178

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 12-49957292-T-C is Benign according to our data. Variant chr12-49957292-T-C is described in ClinVar as Benign. ClinVar VariationId is 309257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
AQP2	NM_000486.6	MANE Select	c.*1684T>C	3_prime_UTR	Exon 4 of 4	NP_000477.1	P41181
AQP5-AS1	NR_110590.1		n.257-2944A>G	intron	N/A
AQP5-AS1	NR_110591.1		n.118-5204A>G	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AQP2	ENST00000199280.4	TSL:1 MANE Select	c.*1684T>C	3_prime_UTR	Exon 4 of 4	ENSP00000199280.3	P41181
AQP5-AS1	ENST00000550530.1	TSL:3	n.118-5204A>G	intron	N/A
AQP2	ENST00000551526.5	TSL:5	n.*115-196T>C	intron	N/A	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53118

AN:

151846

Hom.:

10114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.607

Gnomad SAS

AF:

0.640

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.366

GnomAD4 exome

AF:

0.306

AC:

AN:

134

Hom.:

Cov.:

AF XY:

0.344

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.375

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.286

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.256

AC:

AN:

Other (OTH)

AF:

0.375

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.350

AC:

53149

AN:

151964

Hom.:

10123

Cov.:

AF XY:

0.352

AC XY:

26159

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.426

AC:

17663

AN:

41418

American (AMR)

AF:

0.353

AC:

5387

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

1319

AN:

3468

East Asian (EAS)

AF:

0.608

AC:

3128

AN:

5142

South Asian (SAS)

AF:

0.639

AC:

3073

AN:

4810

European-Finnish (FIN)

AF:

0.249

AC:

2643

AN:

10598

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18757

AN:

67946

Other (OTH)

AF:

0.368

AC:

771

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1691

3382

5072

6763

8454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.306

Hom.:

11750

Bravo

AF:

0.354

Asia WGS

AF:

0.566

AC:

1967

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Diabetes insipidus, nephrogenic, autosomal (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.1

(source)

DANN

Benign

0.75

PhyloP100

0.18

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over