12-49955982-C-T

Variant names:

• chr12-49955982-C-T
• rs467323
• NM_000486.6:c.*374C>T

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.*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
• Publications: 17 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]

ENSG00000257378 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
AQP2	NM_000486.6	c.*374C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110590.1	n.257-1634G>A		intron_variant	Intron 1 of 2
AQP5-AS1	NR_110591.1	n.118-3894G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.*374C>T		3_prime_UTR_variant	Exon 4 of 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

African (AFR) AF: 0.202 AC: 1715 AN: 8506

American (AMR) AF: 0.516 AC: 6138 AN: 11894

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 5107 AN: 8282

East Asian (EAS) AF: 0.233 AC: 3830 AN: 16458

South Asian (SAS) AF: 0.337 AC: 11471 AN: 34020

European-Finnish (FIN) AF: 0.722 AC: 10711 AN: 14840

Middle Eastern (MID) AF: 0.563 AC: 1197 AN: 2126

European-Non Finnish (NFE) AF: 0.717 AC: 114932 AN: 160286

Other (OTH) AF: 0.609 AC: 9742 AN: 16004

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

African (AFR) AF: 0.207 AC: 8599 AN: 41484

American (AMR) AF: 0.536 AC: 8187 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2129 AN: 3470

East Asian (EAS) AF: 0.236 AC: 1215 AN: 5158

South Asian (SAS) AF: 0.324 AC: 1560 AN: 4820

European-Finnish (FIN) AF: 0.702 AC: 7446 AN: 10608

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48838 AN: 67968

Other (OTH) AF: 0.552 AC: 1163 AN: 2108

Alfa AF: 0.667 Hom.: 38897

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.51
PhyloP100		0.52
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: rs467323; hg19: chr12-50349765;