rs3741559

Positions:

• chr12-49951193-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000486.6(AQP2):​c.360+3G>A variant causes a splice donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.00003329
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.58

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]

ACMG classification

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	UniProt
AQP2	NM_000486.6	c.360+3G>A		splice_donor_region_variant, intron_variant		ENST00000199280.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP2	ENST00000199280.4	c.360+3G>A		splice_donor_region_variant, intron_variant		1	NM_000486.6	P1
AQP2	ENST00000550862.1	c.360+3G>A		splice_donor_region_variant, intron_variant		5
AQP2	ENST00000551526.5	c.360+3G>A		splice_donor_region_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25929 AN: 152132 Hom.: 2539 Cov.: 33

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

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.: 33 AF XY: 0.193 AC XY: 138660 AN XY: 719146

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.: 33 AF XY: 0.173 AC XY: 12841 AN XY: 74412

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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	-	- -

not specified Benign:2

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

not provided Benign:2

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	Invitae	Feb 01, 2024	- -

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	17
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

Other links and lift over

dbSNP: rs3741559; hg19: chr12-50344976; COSMIC: COSV52229613; COSMIC: COSV52229613;