Genetic Variant NM_000486.6:c.360+327G>A (chr12-49951517-G-A) – 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.360+327G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 349,918 control chromosomes in the GnomAD database, including 4,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2055 hom., cov: 33)

Exomes 𝑓: 0.11 ( 1968 hom. )

Consequence

AQP2
NM_000486.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.460

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:

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=-0.89).

BP6

Variant 12-49951517-G-A is Benign according to our data. Variant chr12-49951517-G-A is described in ClinVar as Benign. ClinVar VariationId is 1221038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP2	NM_000486.6 link	c.360+327G>A		intron_variant	Intron 1 of 3	ENST00000199280.4	NP_000477.1	P41181
AQP5-AS1	NR_110591.1 link	n.440C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
AQP2	ENST00000199280.4 link	c.360+327G>A	intron_variant	Intron 1 of 3	1	NM_000486.6	ENSP00000199280.3	P41181
AQP5-AS1	ENST00000550530.1 link	n.440C>T	non_coding_transcript_exon_variant	Exon 3 of 3	3
AQP2	ENST00000550862.1 link	c.360+327G>A	intron_variant	Intron 1 of 2	5		ENSP00000450022.1	F8VPL3
AQP2	ENST00000551526.5 link	n.360+327G>A	intron_variant	Intron 1 of 5	5		ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

21339

AN:

152070

Hom.:

2042

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.240

Gnomad ASJ

AF:

0.0792

Gnomad EAS

AF:

0.228

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.0721

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0756

Gnomad OTH

AF:

0.123

GnomAD4 exome

AF:

0.114

AC:

22574

AN:

197730

Hom.:

1968

Cov.:

AF XY:

0.116

AC XY:

11670

AN XY:

100214

show subpopulations

African (AFR)

AF:

0.206

AC:

1540

AN:

7458

American (AMR)

AF:

0.252

AC:

2123

AN:

8418

Ashkenazi Jewish (ASJ)

AF:

0.0811

AC:

588

AN:

7246

East Asian (EAS)

AF:

0.255

AC:

4170

AN:

16330

South Asian (SAS)

AF:

0.319

AC:

2593

AN:

8134

European-Finnish (FIN)

AF:

0.0696

AC:

870

AN:

12494

Middle Eastern (MID)

AF:

0.100

AC:

AN:

986

European-Non Finnish (NFE)

AF:

0.0740

AC:

9178

AN:

123970

Other (OTH)

AF:

0.111

AC:

1413

AN:

12694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

879

1758

2637

3516

4395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

194

388

582

776

970

<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:

0.140

AC:

21379

AN:

152188

Hom.:

2055

Cov.:

AF XY:

0.143

AC XY:

10659

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.203

AC:

8435

AN:

41514

American (AMR)

AF:

0.240

AC:

3675

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0792

AC:

275

AN:

3472

East Asian (EAS)

AF:

0.229

AC:

1184

AN:

5174

South Asian (SAS)

AF:

0.321

AC:

1546

AN:

4812

European-Finnish (FIN)

AF:

0.0721

AC:

764

AN:

10602

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0756

AC:

5144

AN:

68002

Other (OTH)

AF:

0.128

AC:

270

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

894

1789

2683

3578

4472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.108

Hom.:

168

Bravo

AF:

0.151

Asia WGS

AF:

0.308

AC:

1070

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.8

(source)

DANN

Benign

0.70

PhyloP100

-0.46

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over