chr12-49957170-T-C

Variant names:

• chr12-49957170-T-C
• rs296766
• NM_000486.6:c.*1562T>C

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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.86
• Publications: 15 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)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 309255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP2	NM_000486.6	c.*1562T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110590.1	n.257-2822A>G		intron_variant	Intron 1 of 2
AQP5-AS1	NR_110591.1	n.118-5082A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.*1562T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_000486.6	ENSP00000199280.3
AQP5-AS1	ENST00000550530.1	n.118-5082A>G		intron_variant	Intron 1 of 2	3
AQP2	ENST00000551526.5	n.*115-318T>C		intron_variant	Intron 5 of 5	5		ENSP00000447148.1
AQP5-AS1	ENST00000552379.1	n.257-2822A>G		intron_variant	Intron 1 of 2	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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.972 AC: 140 AN: 144

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 1.00 AC: 4 AN: 4

Other (OTH) AF: 1.00 AC: 2 AN: 2

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

African (AFR) AF: 0.756 AC: 31407 AN: 41520

American (AMR) AF: 0.963 AC: 14743 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 3447 AN: 3472

East Asian (EAS) AF: 0.874 AC: 4522 AN: 5174

South Asian (SAS) AF: 0.972 AC: 4692 AN: 4828

European-Finnish (FIN) AF: 0.965 AC: 10248 AN: 10622

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.995 AC: 67700 AN: 68038

Other (OTH) AF: 0.952 AC: 2013 AN: 2114

Alfa AF: 0.959 Hom.: 123808

Bravo AF: 0.911

Asia WGS AF: 0.911 AC: 3169 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Diabetes insipidus, nephrogenic, autosomal Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.34
DANN	Benign	0.50
PhyloP100		-1.9
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: rs296766; hg19: chr12-50350953;