12-49957170-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000486.6(AQP2):c.*1562T>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 0.919 in 152,436 control chromosomes in the GnomAD database, including 65,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.92 (65135 hom., cov: 33)
  • Exomes 𝑓: 0.97 (72 hom.)
• Consequence: AQP2 NM_000486.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.86

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)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-49957170-T-C is Benign according to our data. Variant chr12-49957170-T-C is described in ClinVar as [Benign]. Clinvar id is 309255.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP2	NM_000486.6	c.*1562T>C		3_prime_UTR_variant	4/4	ENST00000199280.4
AQP5-AS1	NR_110591.1	n.118-5082A>G		intron_variant, non_coding_transcript_variant
AQP5-AS1	NR_110590.1	n.257-2822A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP2	ENST00000199280.4	c.*1562T>C		3_prime_UTR_variant	4/4	1	NM_000486.6	P1
AQP5-AS1	ENST00000550530.1	n.118-5082A>G		intron_variant, non_coding_transcript_variant		3
AQP2	ENST00000551526.5	c.*115-318T>C		intron_variant, NMD_transcript_variant		5
AQP5-AS1	ENST00000552379.1	n.257-2822A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.919 AC: 139868 AN: 152166 Hom.: 65085 Cov.: 33

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.963

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.972

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.995

Gnomad OTH AF: 0.952

GnomAD4 exome AF: 0.974 AC: 148 AN: 152 Hom.: 72 Cov.: 0 AF XY: 0.953 AC XY: 82 AN XY: 86

Gnomad4 FIN exome AF: 0.972

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.919 AC: 139973 AN: 152284 Hom.: 65135 Cov.: 33 AF XY: 0.919 AC XY: 68408 AN XY: 74468

Gnomad4 AFR AF: 0.756

Gnomad4 AMR AF: 0.963

Gnomad4 ASJ AF: 0.993

Gnomad4 EAS AF: 0.874

Gnomad4 SAS AF: 0.972

Gnomad4 FIN AF: 0.965

Gnomad4 NFE AF: 0.995

Gnomad4 OTH AF: 0.952

Alfa AF: 0.957 Hom.: 19015

Bravo AF: 0.911

Asia WGS AF: 0.911 AC: 3169 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.88
Cadd	Benign	0.34
Dann	Benign	0.50

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: rs296766; hg19: chr12-50350953;