rs3741559

Positions:

chr12-49951193-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000486.6(AQP2):c.360+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,600,584 control chromosomes in the GnomAD database, including 30,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2535 hom., cov: 33)

Exomes 𝑓: 0.19 ( 28003 hom. )

Consequence

AQP2
NM_000486.6 splice_region, intron

Scores

Splicing: ADA: 0.00003329

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 12-49951193-G-A is Benign according to our data. Variant chr12-49951193-G-A is described in ClinVar as [Benign]. Clinvar id is 256243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49951193-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6 link	c.360+3G>A		splice_region_variant, intron_variant		ENST00000199280.4	NP_000477.1	P41181

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
AQP2	ENST00000199280.4 link	c.360+3G>A	splice_region_variant, intron_variant	1	NM_000486.6	ENSP00000199280.3	P41181
AQP2	ENST00000550862.1 link	c.360+3G>A	splice_region_variant, intron_variant	5		ENSP00000450022.1	F8VPL3
AQP2	ENST00000551526.5 link	n.360+3G>A	splice_region_variant, intron_variant	5		ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25929

AN:

152132

Hom.:

2539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.219

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.192

GnomAD3 exomes

AF:

0.197

AC:

45710

AN:

232494

Hom.:

5294

AF XY:

0.206

AC XY:

26032

AN XY:

126564

show subpopulations

Gnomad AFR exome

AF:

0.127

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.370

Gnomad SAS exome

AF:

0.313

Gnomad FIN exome

AF:

0.157

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.200

GnomAD4 exome

AF:

0.188

AC:

272814

AN:

1448332

Hom.:

28003

Cov.:

AF XY:

0.193

AC XY:

138660

AN XY:

719146

show subpopulations

Gnomad4 AFR exome

AF:

0.123

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.246

Gnomad4 EAS exome

AF:

0.367

Gnomad4 SAS exome

AF:

0.315

Gnomad4 FIN exome

AF:

0.155

Gnomad4 NFE exome

AF:

0.176

Gnomad4 OTH exome

AF:

0.208

GnomAD4 genome

AF:

0.170

AC:

25920

AN:

152252

Hom.:

2535

Cov.:

AF XY:

0.173

AC XY:

12841

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.249

Gnomad4 EAS

AF:

0.358

Gnomad4 SAS

AF:

0.321

Gnomad4 FIN

AF:

0.155

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.184

Hom.:

6295

Bravo

AF:

0.161

Asia WGS

AF:

0.262

AC:

910

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 27884173, 20814834) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nephrogenic diabetes insipidus

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000033

dbscSNV1_RF

Benign

0.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over