Genetic Variant AQP2:c.607-39C>G (chr12-49955360-C-G) – 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.607-39C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 1,598,764 control chromosomes in the GnomAD database, including 495,797 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 40090 hom., cov: 34)

Exomes 𝑓: 0.79 ( 455707 hom. )

Consequence

AQP2
NM_000486.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.05

Publications

7 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:

ENSG00000257378 (HGNC:):

ENSG00000257378 links:

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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=-0.87).

BP6

Variant 12-49955360-C-G is Benign according to our data. Variant chr12-49955360-C-G is described in ClinVar as Benign. ClinVar VariationId is 1180579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.807 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.607-39C>G	intron	N/A	NP_000477.1	P41181
AQP5-AS1	NR_110590.1		n.257-1012G>C	intron	N/A
AQP5-AS1	NR_110591.1		n.118-3272G>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AQP2	ENST00000199280.4	TSL:1 MANE Select	c.607-39C>G	intron	N/A	ENSP00000199280.3	P41181
AQP5-AS1	ENST00000550530.1	TSL:3	n.118-3272G>C	intron	N/A
AQP2	ENST00000551526.5	TSL:5	n.607-39C>G	intron	N/A	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes

AF:

0.710

AC:

107974

AN:

152118

Hom.:

40053

Cov.:

show subpopulations

Gnomad AFR

AF:

0.483

Gnomad AMI

AF:

0.774

Gnomad AMR

AF:

0.818

Gnomad ASJ

AF:

0.730

Gnomad EAS

AF:

0.638

Gnomad SAS

AF:

0.693

Gnomad FIN

AF:

0.844

Gnomad MID

AF:

0.685

Gnomad NFE

AF:

0.807

Gnomad OTH

AF:

0.717

GnomAD2 exomes

AF:

0.772

AC:

174849

AN:

226392

AF XY:

0.769

show subpopulations

Gnomad AFR exome

AF:

0.473

Gnomad AMR exome

AF:

0.877

Gnomad ASJ exome

AF:

0.737

Gnomad EAS exome

AF:

0.630

Gnomad FIN exome

AF:

0.845

Gnomad NFE exome

AF:

0.808

Gnomad OTH exome

AF:

0.776

GnomAD4 exome

AF:

0.791

AC:

1143716

AN:

1446528

Hom.:

455707

Cov.:

AF XY:

0.788

AC XY:

566100

AN XY:

718118

show subpopulations

African (AFR)

AF:

0.470

AC:

15500

AN:

32948

American (AMR)

AF:

0.867

AC:

38205

AN:

44058

Ashkenazi Jewish (ASJ)

AF:

0.733

AC:

18893

AN:

25784

East Asian (EAS)

AF:

0.633

AC:

24789

AN:

39154

South Asian (SAS)

AF:

0.699

AC:

59538

AN:

85194

European-Finnish (FIN)

AF:

0.845

AC:

43523

AN:

51478

Middle Eastern (MID)

AF:

0.685

AC:

3466

AN:

5062

European-Non Finnish (NFE)

AF:

0.811

AC:

894667

AN:

1103350

Other (OTH)

AF:

0.759

AC:

45135

AN:

59500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

13034

26068

39101

52135

65169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20688

41376

62064

82752

103440

<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:

0.710

AC:

108064

AN:

152236

Hom.:

40090

Cov.:

AF XY:

0.712

AC XY:

53043

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.483

AC:

20065

AN:

41534

American (AMR)

AF:

0.819

AC:

12530

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.730

AC:

2533

AN:

3472

East Asian (EAS)

AF:

0.637

AC:

3289

AN:

5160

South Asian (SAS)

AF:

0.693

AC:

3347

AN:

4828

European-Finnish (FIN)

AF:

0.844

AC:

8964

AN:

10622

Middle Eastern (MID)

AF:

0.682

AC:

199

AN:

292

European-Non Finnish (NFE)

AF:

0.807

AC:

54907

AN:

67998

Other (OTH)

AF:

0.721

AC:

1524

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1495

2990

4486

5981

7476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.754

Hom.:

8143

Bravo

AF:

0.701

Asia WGS

AF:

0.736

AC:

2560

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Diabetes insipidus, nephrogenic, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.61

(source)

DANN

Benign

0.069

PhyloP100

-3.1

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