chr12-49951423-G-A

Variant names:

• chr12-49951423-G-A
• rs461872
• NM_000486.6:c.360+233G>A

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.360+233G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 611,596 control chromosomes in the GnomAD database, including 66,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13797 hom., cov: 32)
  • Exomes 𝑓: 0.46 (52306 hom.)
• Consequence: AQP2 NM_000486.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.52
• Publications: 12 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=-0.87).
• BP6: Variant 12-49951423-G-A is Benign according to our data. Variant chr12-49951423-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000486.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	NM_000486.6	MANE Select	c.360+233G>A		intron	N/A	NP_000477.1
	AQP5-AS1	NR_110591.1		n.*89C>T		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	ENST00000199280.4	TSL:1 MANE Select	c.360+233G>A		intron	N/A	ENSP00000199280.3
	AQP2	ENST00000550862.1	TSL:5	c.360+233G>A		intron	N/A	ENSP00000450022.1
	AQP2	ENST00000551526.5	TSL:5	n.360+233G>A		intron	N/A	ENSP00000447148.1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60686 AN: 151988 Hom.: 13789 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.418

GnomAD4 exome AF: 0.460 AC: 211279 AN: 459490 Hom.: 52306 AF XY: 0.454 AC XY: 106397 AN XY: 234362

African (AFR) AF: 0.186 AC: 2432 AN: 13082

American (AMR) AF: 0.403 AC: 6826 AN: 16954

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 4550 AN: 12966

East Asian (EAS) AF: 0.206 AC: 6223 AN: 30248

South Asian (SAS) AF: 0.242 AC: 7481 AN: 30876

European-Finnish (FIN) AF: 0.572 AC: 15557 AN: 27216

Middle Eastern (MID) AF: 0.385 AC: 743 AN: 1928

European-Non Finnish (NFE) AF: 0.520 AC: 156191 AN: 300386

Other (OTH) AF: 0.436 AC: 11276 AN: 25834

GnomAD4 genome AF: 0.399 AC: 60706 AN: 152106 Hom.: 13797 Cov.: 32 AF XY: 0.397 AC XY: 29513 AN XY: 74364

African (AFR) AF: 0.198 AC: 8203 AN: 41490

American (AMR) AF: 0.405 AC: 6199 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3470

East Asian (EAS) AF: 0.223 AC: 1152 AN: 5174

South Asian (SAS) AF: 0.228 AC: 1102 AN: 4826

European-Finnish (FIN) AF: 0.555 AC: 5867 AN: 10566

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35515 AN: 67972

Other (OTH) AF: 0.414 AC: 871 AN: 2106

Alfa AF: 0.478 Hom.: 29480

Bravo AF: 0.382

Asia WGS AF: 0.209 AC: 727 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.37
DANN	Benign	0.45
PhyloP100		-1.5
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: rs461872; hg19: chr12-50345206;