12-49955982-C-T

Position:

• chr12-49955982-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000486.6(AQP2):​c.*374C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 424,518 control chromosomes in the GnomAD database, including 79,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (25039 hom., cov: 32)
  • Exomes 𝑓: 0.61 (54437 hom.)
• Consequence: AQP2 NM_000486.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.521

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]

ENSG00000257378 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-49955982-C-T is Benign according to our data. Variant chr12-49955982-C-T is described in ClinVar as [Benign]. Clinvar id is 309241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6	c.*374C>T		3_prime_UTR_variant	4/4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110590.1	n.257-1634G>A		intron_variant
AQP5-AS1	NR_110591.1	n.118-3894G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.*374C>T		3_prime_UTR_variant	4/4	1	NM_000486.6	ENSP00000199280.3

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79899 AN: 151986 Hom.: 25033 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.605 AC: 164843 AN: 272416 Hom.: 54437 Cov.: 0 AF XY: 0.586 AC XY: 83288 AN XY: 142038

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.516

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.722

Gnomad4 NFE exome AF: 0.717

Gnomad4 OTH exome AF: 0.609

GnomAD4 genome AF: 0.526 AC: 79932 AN: 152102 Hom.: 25039 Cov.: 32 AF XY: 0.521 AC XY: 38764 AN XY: 74384

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.702

Gnomad4 NFE AF: 0.719

Gnomad4 OTH AF: 0.552

Alfa AF: 0.672 Hom.: 33278

Bravo AF: 0.504

Asia WGS AF: 0.319 AC: 1110 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.51

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: rs467323; hg19: chr12-50349765;