Variant chr12-49954672-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000486.6(AQP2):c.568G>A(p.Ala190Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AQP2
NM_000486.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.77

Variant links:

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]

AQP2 links:

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

AQP5-AS1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a chain Aquaporin-2 (size 270) in uniprot entity AQP2_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_000486.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 12-49954672-G-A is Pathogenic according to our data. Variant chr12-49954672-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17845.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AQP2	NM_000486.6 linkuse as main transcript	c.568G>A	p.Ala190Thr	missense_variant	3/4	ENST00000199280.4	NP_000477.1
AQP5-AS1	NR_110591.1 linkuse as main transcript	n.118-2584C>T		intron_variant, non_coding_transcript_variant
AQP5-AS1	NR_110590.1 linkuse as main transcript	n.257-324C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
AQP2	ENST00000199280.4 linkuse as main transcript	c.568G>A	p.Ala190Thr	missense_variant	3/4	1	NM_000486.6	ENSP00000199280	P1
AQP5-AS1	ENST00000550530.1 linkuse as main transcript	n.118-2584C>T		intron_variant, non_coding_transcript_variant		3
	ENST00000552806.1 linkuse as main transcript	n.542-15C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;T

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

0.36

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.5

D;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.0030

B;.

Vest4

0.55

MutPred

0.96

Gain of phosphorylation at A190 (P = 0.0454);.;

MVP

0.99

MPC

0.52

ClinPred

0.96

GERP RS

4.4

Varity_R

0.67

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over