12-49957292-T-C

Position:

• chr12-49957292-T-C

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.*1684T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,098 control chromosomes in the GnomAD database, including 10,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10123 hom., cov: 32)
  • Exomes 𝑓: 0.31 (9 hom.)
• Consequence: AQP2 NM_000486.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.178

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-49957292-T-C is Benign according to our data. Variant chr12-49957292-T-C is described in ClinVar as [Benign]. Clinvar id is 309257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6	c.*1684T>C		3_prime_UTR_variant	4/4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110590.1	n.257-2944A>G		intron_variant
AQP5-AS1	NR_110591.1	n.118-5204A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.*1684T>C		3_prime_UTR_variant	4/4	1	NM_000486.6	ENSP00000199280.3
AQP5-AS1	ENST00000550530.1	n.118-5204A>G		intron_variant		3
AQP2	ENST00000551526.5	n.*115-196T>C		intron_variant		5		ENSP00000447148.1
AQP5-AS1	ENST00000552379.1	n.257-2944A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53118 AN: 151846 Hom.: 10114 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.306 AC: 41 AN: 134 Hom.: 9 Cov.: 0 AF XY: 0.344 AC XY: 33 AN XY: 96

Gnomad4 AFR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.350 AC: 53149 AN: 151964 Hom.: 10123 Cov.: 32 AF XY: 0.352 AC XY: 26159 AN XY: 74284

Gnomad4 AFR AF: 0.426

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.608

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.368

Alfa AF: 0.307 Hom.: 1498

Bravo AF: 0.354

Asia WGS AF: 0.566 AC: 1967 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Diabetes insipidus, nephrogenic, autosomal Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.75

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: rs10875989; hg19: chr12-50351075;