Genetic Variant AQP6:p.Asn133Lys (chr12-49973572-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001652.4(AQP6):c.399C>A(p.Asn133Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000563 in 1,598,334 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 Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

AQP6
NM_001652.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.18

Variant links:

Genes affected

AQP6 (HGNC:639): (aquaporin 6) The protein encoded by this gene is an aquaporin protein, which functions as a water channel in cells. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). This protein is specific for the kidney. This gene and related family members AQP0, AQP2, and AQP5 reside in a cluster on chromosome 12q13. [provided by RefSeq, Jul 2008]

AQP6 links:

LOC105369764 (HGNC:):

LOC105369764 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP6	NM_001652.4 link	c.399C>A	p.Asn133Lys	missense_variant	Exon 1 of 4	ENST00000315520.10	NP_001643.2	Q13520
LOC105369764	XR_001749143.2 link	n.208+1726G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AQP6	ENST00000315520.10 link	c.399C>A	p.Asn133Lys	missense_variant	Exon 1 of 4	1	NM_001652.4	ENSP00000320247.5	Q13520
AQP6	ENST00000489786.5 link	n.2412C>A		non_coding_transcript_exon_variant	Exon 4 of 7	1
AQP6	ENST00000618286.1 link	c.399C>A	p.Asn133Lys	missense_variant	Exon 1 of 2	5		ENSP00000477759.1	Q9NSV5
AQP6	ENST00000551733.5 link	c.-120-752C>A		intron_variant	Intron 3 of 5	3		ENSP00000449830.1	F8VW87

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152160

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000458

AC:

AN:

218546

Hom.:

AF XY:

0.00

AC XY:

AN XY:

118874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1446174

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717936

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:

0.00000362

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.399C>A (p.N133K) alteration is located in exon 1 (coding exon 1) of the AQP6 gene. This alteration results from a C to A substitution at nucleotide position 399, causing the asparagine (N) at amino acid position 133 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

1.2

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;D;D

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.51

T;.;T

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.3

.;M;M

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.6

.;D;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

.;D;.

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.67

MutPred

0.62

Gain of methylation at N133 (P = 0.009);Gain of methylation at N133 (P = 0.009);Gain of methylation at N133 (P = 0.009);

MVP

0.89

MPC

0.92

ClinPred

0.99

GERP RS

-5.1

Varity_R

0.93

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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