12-49955360-C-G

Variant names:

• chr12-49955360-C-G
• rs403201
• NM_000486.6:c.607-39C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000486.6(AQP2):​c.607-39C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 1,598,764 control chromosomes in the GnomAD database, including 495,797 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (40090 hom., cov: 34)
  • Exomes 𝑓: 0.79 (455707 hom.)
• Consequence: AQP2 NM_000486.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.05
• Publications: 7 publications found

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)

ENSG00000257378 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-49955360-C-G is Benign according to our data. Variant chr12-49955360-C-G is described in ClinVar as Benign. ClinVar VariationId is 1180579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AQP2	NM_000486.6	c.607-39C>G		intron_variant	Intron 3 of 3	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110590.1	n.257-1012G>C		intron_variant	Intron 1 of 2
AQP5-AS1	NR_110591.1	n.118-3272G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.607-39C>G		intron_variant	Intron 3 of 3	1	NM_000486.6	ENSP00000199280.3

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107974 AN: 152118 Hom.: 40053 Cov.: 34

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.717

GnomAD2 exomes AF: 0.772 AC: 174849 AN: 226392 AF XY: 0.769

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.877

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.630

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.808

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.791 AC: 1143716 AN: 1446528 Hom.: 455707 Cov.: 36 AF XY: 0.788 AC XY: 566100 AN XY: 718118

African (AFR) AF: 0.470 AC: 15500 AN: 32948

American (AMR) AF: 0.867 AC: 38205 AN: 44058

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 18893 AN: 25784

East Asian (EAS) AF: 0.633 AC: 24789 AN: 39154

South Asian (SAS) AF: 0.699 AC: 59538 AN: 85194

European-Finnish (FIN) AF: 0.845 AC: 43523 AN: 51478

Middle Eastern (MID) AF: 0.685 AC: 3466 AN: 5062

European-Non Finnish (NFE) AF: 0.811 AC: 894667 AN: 1103350

Other (OTH) AF: 0.759 AC: 45135 AN: 59500

GnomAD4 genome AF: 0.710 AC: 108064 AN: 152236 Hom.: 40090 Cov.: 34 AF XY: 0.712 AC XY: 53043 AN XY: 74456

African (AFR) AF: 0.483 AC: 20065 AN: 41534

American (AMR) AF: 0.819 AC: 12530 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2533 AN: 3472

East Asian (EAS) AF: 0.637 AC: 3289 AN: 5160

South Asian (SAS) AF: 0.693 AC: 3347 AN: 4828

European-Finnish (FIN) AF: 0.844 AC: 8964 AN: 10622

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.807 AC: 54907 AN: 67998

Other (OTH) AF: 0.721 AC: 1524 AN: 2114

Alfa AF: 0.754 Hom.: 8143

Bravo AF: 0.701

Asia WGS AF: 0.736 AC: 2560 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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

- -

Diabetes insipidus, nephrogenic, autosomal Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.61
DANN	Benign	0.069
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs403201; hg19: chr12-50349143; COSMIC: COSV52230562; COSMIC: COSV52230562;