rs104894332

Variant names:

• chr12-49955564-G-A
• rs104894332
• NM_000486.6:c.772G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000486.6(AQP2):​c.772G>A​(p.Glu258Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AQP2 NM_000486.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.79
• Publications: 24 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)

ENSG00000257378 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Aquaporin-2 (size 270) in uniprot entity AQP2_HUMAN there are 29 pathogenic changes around while only 8 benign (78%) in NM_000486.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49955564-G-A is Pathogenic according to our data. Variant chr12-49955564-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17836.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	NM_000486.6	MANE Select	c.772G>A	p.Glu258Lys	missense	Exon 4 of 4	NP_000477.1	P41181
	AQP5-AS1	NR_110590.1		n.257-1216C>T		intron	N/A
	AQP5-AS1	NR_110591.1		n.118-3476C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	ENST00000199280.4	TSL:1 MANE Select	c.772G>A	p.Glu258Lys	missense	Exon 4 of 4	ENSP00000199280.3	P41181
	AQP5-AS1	ENST00000550530.1	TSL:3	n.118-3476C>T		intron	N/A
	AQP2	ENST00000551526.5	TSL:5	n.631+141G>A		intron	N/A	ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Diabetes insipidus, nephrogenic, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.81
Sift	Benign	0.18	T
Sift4G	Uncertain	0.028	D
Polyphen		0.98	D
Vest4		0.44
MutPred		0.77		Gain of MoRF binding (P = 0.006)
MVP		0.95
MPC		1.5
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.27
gMVP		0.82
Mutation Taster		=48/52	disease causing (ClinVar)

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: rs104894332; hg19: chr12-50349347;