chr12-49950862-G-A

Position:

chr12-49950862-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS1_Supporting

The NM_000486.6(AQP2):c.32G>A(p.Arg11Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000676 in 1,613,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

AQP2
NM_000486.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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

BP4

Computational evidence support a benign effect (MetaRNN=0.14614972).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000719 (105/1460974) while in subpopulation EAS AF= 0.00262 (104/39640). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4_exome. There are 60 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP2	NM_000486.6 linkuse as main transcript	c.32G>A	p.Arg11Lys	missense_variant	1/4	ENST00000199280.4	NP_000477.1	P41181

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AQP2	ENST00000199280.4 linkuse as main transcript	c.32G>A	p.Arg11Lys	missense_variant	1/4	1	NM_000486.6	ENSP00000199280.3	P41181
AQP2	ENST00000550862.1 linkuse as main transcript	c.32G>A	p.Arg11Lys	missense_variant	1/3	5		ENSP00000450022.1	F8VPL3
AQP2	ENST00000551526.5 linkuse as main transcript	n.32G>A		non_coding_transcript_exon_variant	1/6	5		ENSP00000447148.1	F8W0S2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251274

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000719

AC:

105

AN:

1460974

Hom.:

Cov.:

AF XY:

0.0000826

AC XY:

AN XY:

726592

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00262

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000262

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74528

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Diabetes insipidus, nephrogenic, autosomal

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;D

Eigen

Benign

-0.037

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.0

L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.27

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.039

B;.

Vest4

0.43

MVP

0.89

MPC

0.54

ClinPred

0.20

GERP RS

4.4

Varity_R

0.53

gMVP

0.68

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