12-49958610-G-C

Variant names:

• chr12-49958610-G-C
• rs2878771
• NM_000486.6:c.*3002G>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.*3002G>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 0.183 in 152,284 control chromosomes in the GnomAD database, including 2,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2800 hom., cov: 33)
  • Exomes 𝑓: 0.20 (1 hom.)
• Consequence: AQP2 NM_000486.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.67
• Publications: 18 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=-0.81).
• BP6: Variant 12-49958610-G-C is Benign according to our data. Variant chr12-49958610-G-C is described in ClinVar as Benign. ClinVar VariationId is 309270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP2	NM_000486.6	c.*3002G>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110590.1	n.256+4057C>G		intron_variant	Intron 1 of 2
AQP5-AS1	NR_110591.1	n.117+4057C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.*3002G>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_000486.6	ENSP00000199280.3
AQP5-AS1	ENST00000550530.1	n.117+4057C>G		intron_variant	Intron 1 of 2	3
AQP5-AS1	ENST00000552379.1	n.256+4057C>G		intron_variant	Intron 1 of 2	3
AQP2	ENST00000551526.5	n.*1237G>C		downstream_gene_variant		5		ENSP00000447148.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27883 AN: 152104 Hom.: 2801 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.200 AC: 12 AN: 60 Hom.: 1 Cov.: 0 AF XY: 0.222 AC XY: 12 AN XY: 54

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

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: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.205 AC: 9 AN: 44

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.183 AC: 27884 AN: 152224 Hom.: 2800 Cov.: 33 AF XY: 0.185 AC XY: 13792 AN XY: 74432

African (AFR) AF: 0.152 AC: 6316 AN: 41526

American (AMR) AF: 0.141 AC: 2154 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 865 AN: 3470

East Asian (EAS) AF: 0.364 AC: 1887 AN: 5180

South Asian (SAS) AF: 0.320 AC: 1541 AN: 4816

European-Finnish (FIN) AF: 0.179 AC: 1903 AN: 10608

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12533 AN: 68008

Other (OTH) AF: 0.211 AC: 446 AN: 2116

Alfa AF: 0.104 Hom.: 168

Bravo AF: 0.175

Asia WGS AF: 0.250 AC: 869 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 12, 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	-0.81
CADD	Benign	6.8
DANN	Benign	0.52
PhyloP100		1.7
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: rs2878771; hg19: chr12-50352393;