12-49950869-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000486.6(AQP2):c.39G>A(p.Val13=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,613,494 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (51 hom.)
• Consequence: AQP2 NM_000486.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.55

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-49950869-G-A is Benign according to our data. Variant chr12-49950869-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49950869-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0055 (838/152400) while in subpopulation AMR AF= 0.0104 (160/15314). AF 95% confidence interval is 0.00913. There are 2 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP2	NM_000486.6	c.39G>A	p.Val13=	synonymous_variant	1/4	ENST00000199280.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP2	ENST00000199280.4	c.39G>A	p.Val13=	synonymous_variant	1/4	1	NM_000486.6	P1
AQP2	ENST00000550862.1	c.39G>A	p.Val13=	synonymous_variant	1/3	5
AQP2	ENST00000551526.5	c.39G>A	p.Val13=	synonymous_variant, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 837 AN: 152282 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00704

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00590 AC: 1482 AN: 251302 Hom.: 8 AF XY: 0.00637 AC XY: 865 AN XY: 135846

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00790

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00753

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00672 AC: 9818 AN: 1461094 Hom.: 51 Cov.: 31 AF XY: 0.00690 AC XY: 5013 AN XY: 726668

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00653

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00815

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00698

Gnomad4 OTH exome AF: 0.00797

GnomAD4 genome AF: 0.00550 AC: 838 AN: 152400 Hom.: 2 Cov.: 33 AF XY: 0.00535 AC XY: 399 AN XY: 74538

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00765

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00704

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00738 Hom.: 3

Bravo AF: 0.00634

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0105

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	AQP2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Diabetes insipidus, nephrogenic, autosomal Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nephrogenic diabetes insipidus Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.6
Dann	Benign	0.80

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: rs61733029; hg19: chr12-50344652;