rs426496

Positions:

• chr12-49954295-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000486.6(AQP2):​c.501T>C​(p.Ser167=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 1,608,946 control chromosomes in the GnomAD database, including 498,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (40074 hom., cov: 31)
  • Exomes 𝑓: 0.79 (458430 hom.)
• Consequence: AQP2 NM_000486.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.37

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]

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-49954295-T-C is Benign according to our data. Variant chr12-49954295-T-C is described in ClinVar as [Benign]. Clinvar id is 504917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49954295-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6	c.501T>C	p.Ser167=	synonymous_variant	2/4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110591.1	n.118-2207A>G		intron_variant, non_coding_transcript_variant
AQP5-AS1	NR_110590.1	n.310A>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.501T>C	p.Ser167=	synonymous_variant	2/4	1	NM_000486.6	ENSP00000199280	P1
AQP5-AS1	ENST00000550530.1	n.118-2207A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107887 AN: 151888 Hom.: 40036 Cov.: 31

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.718

GnomAD3 exomes AF: 0.766 AC: 188673 AN: 246408 Hom.: 73696 AF XY: 0.765 AC XY: 102254 AN XY: 133686

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.875

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.627

Gnomad SAS exome AF: 0.700

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.806

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.790 AC: 1151098 AN: 1456940 Hom.: 458430 Cov.: 68 AF XY: 0.788 AC XY: 570946 AN XY: 724942

Gnomad4 AFR exome AF: 0.470

Gnomad4 AMR exome AF: 0.866

Gnomad4 ASJ exome AF: 0.732

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.698

Gnomad4 FIN exome AF: 0.844

Gnomad4 NFE exome AF: 0.811

Gnomad4 OTH exome AF: 0.758

GnomAD4 genome AF: 0.710 AC: 107978 AN: 152006 Hom.: 40074 Cov.: 31 AF XY: 0.713 AC XY: 52979 AN XY: 74306

Gnomad4 AFR AF: 0.484

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.730

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.694

Gnomad4 FIN AF: 0.844

Gnomad4 NFE AF: 0.808

Gnomad4 OTH AF: 0.722

Alfa AF: 0.775 Hom.: 18405

Bravo AF: 0.702

Asia WGS AF: 0.737 AC: 2563 AN: 3478

EpiCase AF: 0.801

EpiControl AF: 0.795

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ser167Ser in exon 2 of AQP2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 88.04% (10065/11432) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs426496). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Diabetes insipidus, nephrogenic, autosomal Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Nephrogenic diabetes insipidus Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.55

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

LitVar

Other links and lift over

dbSNP: rs426496; hg19: chr12-50348078; COSMIC: COSV52229985; COSMIC: COSV52229985;