Genetic Variant AQP8:p.Pro112Leu (chr16-25221531-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001169.3(AQP8):c.335C>T(p.Pro112Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

AQP8
NM_001169.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

Variant links:

Genes affected

AQP8 (HGNC:642): (aquaporin 8) Aquaporin 8 (AQP8) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 8 mRNA is found in pancreas and colon but not other tissues. [provided by RefSeq, Jul 2008]

AQP8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP8	NM_001169.3 link	c.335C>T	p.Pro112Leu	missense_variant	Exon 3 of 6	ENST00000219660.6	NP_001160.2	O94778
AQP8	XM_011545822.3 link	c.338C>T	p.Pro113Leu	missense_variant	Exon 3 of 6		XP_011544124.1
AQP8	XM_011545823.3 link	c.263+4086C>T		intron_variant	Intron 2 of 3		XP_011544125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP8	ENST00000219660.6 link	c.335C>T	p.Pro112Leu	missense_variant	Exon 3 of 6	1	NM_001169.3	ENSP00000219660.5		O94778
AQP8	ENST00000566125.5 link	c.317C>T	p.Pro106Leu	missense_variant	Exon 3 of 6	1		ENSP00000454457.1		A0A0C4DGL6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251448

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000741

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

not specified

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335C>T (p.P112L) alteration is located in exon 3 (coding exon 3) of the AQP8 gene. This alteration results from a C to T substitution at nucleotide position 335, causing the proline (P) at amino acid position 112 to be replaced by a leucine (L). 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

Uncertain

0.35

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

.;D

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.3

.;L

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Uncertain

0.63

Sift

Benign

0.10

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.93

.;P

Vest4

0.47

MutPred

0.52

.;Gain of catalytic residue at P112 (P = 0.0031);

MVP

0.95

MPC

0.38

ClinPred

0.24

GERP RS

5.6

Varity_R

0.23

gMVP

0.90

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