rs104894332

Positions:

• chr12-49955564-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The ENST00000199280.4(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 ENST00000199280.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.79

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)

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest Disordered (size 23) in uniprot entity AQP2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000199280.4
• 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 id is 17836.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6	c.772G>A	p.Glu258Lys	missense_variant	4/4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110591.1	n.118-3476C>T		intron_variant, non_coding_transcript_variant
AQP5-AS1	NR_110590.1	n.257-1216C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.772G>A	p.Glu258Lys	missense_variant	4/4	1	NM_000486.6	ENSP00000199280	P1
AQP5-AS1	ENST00000550530.1	n.118-3476C>T		intron_variant, non_coding_transcript_variant		3
	ENST00000552806.1	n.541+21C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A
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

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: rs104894332; hg19: chr12-50349347;