Genetic Variant AQP2:p.Asn68Thr (chr12-49951033-A-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM5PP3BP4_Strong

The ENST00000199280.4(AQP2):c.203A>C(p.Asn68Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N68S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AQP2
ENST00000199280.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.50

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

diabetes insipidus, nephrogenic, autosomal
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
nephrogenic diabetes insipidus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

AQP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-49951033-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 17834.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.019495219).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000199280.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP2	NM_000486.6	MANE Select	c.203A>C	p.Asn68Thr	missense	Exon 1 of 4	NP_000477.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AQP2	ENST00000199280.4	TSL:1 MANE Select	c.203A>C	p.Asn68Thr	missense	Exon 1 of 4	ENSP00000199280.3
AQP2	ENST00000550862.1	TSL:5	c.203A>C	p.Asn68Thr	missense	Exon 1 of 3	ENSP00000450022.1
AQP2	ENST00000551526.5	TSL:5	n.203A>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000447148.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151816

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0252

AC:

5705

AN:

226550

AF XY:

0.0238

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.0324

Gnomad ASJ exome

AF:

0.00577

Gnomad EAS exome

AF:

0.0343

Gnomad FIN exome

AF:

0.0452

Gnomad NFE exome

AF:

0.0239

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00231

AC:

3333

AN:

1445476

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1754

AN XY:

718174

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00436

AC:

143

AN:

32814

American (AMR)

AF:

0.0241

AC:

1015

AN:

42036

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

25752

East Asian (EAS)

AF:

0.0112

AC:

429

AN:

38360

South Asian (SAS)

AF:

0.00167

AC:

142

AN:

84982

European-Finnish (FIN)

AF:

0.00853

AC:

427

AN:

50058

Middle Eastern (MID)

AF:

0.00321

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.000929

AC:

1028

AN:

1106088

Other (OTH)

AF:

0.00151

AC:

AN:

59774

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.290

Heterozygous variant carriers

295

589

884

1178

1473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000198

AC:

AN:

151816

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74124

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41362

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67840

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000647710), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000733

Hom.:

ExAC

AF:

0.0468

AC:

5676

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.019

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

PhyloP100

7.5

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.81

MPC

1.4

ClinPred

0.063

GERP RS

4.6

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.95

gMVP

0.94

Mutation Taster

=28/72

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over