12-49951033-A-G

Variant names:

• chr12-49951033-A-G
• rs104894331
• NM_000486.6:c.203A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000486.6(AQP2):​c.203A>G​(p.Asn68Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N68Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AQP2 NM_000486.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.50

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a intramembrane_region Discontinuously helical (size 9) in uniprot entity AQP2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000486.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 12-49951033-A-G is Pathogenic according to our data. Variant chr12-49951033-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 17834.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP2	NM_000486.6	c.203A>G	p.Asn68Ser	missense_variant	Exon 1 of 4	ENST00000199280.4	NP_000477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP2	ENST00000199280.4	c.203A>G	p.Asn68Ser	missense_variant	Exon 1 of 4	1	NM_000486.6	ENSP00000199280.3
AQP2	ENST00000550862.1	c.203A>G	p.Asn68Ser	missense_variant	Exon 1 of 3	5		ENSP00000450022.1
AQP2	ENST00000551526.5	n.203A>G		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000447148.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal Pathogenic:1

Feb 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.97		Gain of glycosylation at N68 (P = 0.0184);Gain of glycosylation at N68 (P = 0.0184);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.85
gMVP		0.92

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: rs104894331; hg19: chr12-50344816;