Genetic Variant AQP12A:p.Glu93Lys (chr2-240692227-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_198998.3(AQP12A):c.277G>A(p.Glu93Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000975 in 1,579,342 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000069 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00010 ( 25 hom. )

Consequence

AQP12A
NM_198998.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

Variant links:

Genes affected

AQP12A (HGNC:19941): (aquaporin 12A) Predicted to enable channel activity. Predicted to be involved in transmembrane transport. Predicted to be integral component of membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

AQP12A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04863876).

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP12A	NM_198998.3 link	c.277G>A	p.Glu93Lys	missense_variant	Exon 2 of 4	ENST00000337801.9	NP_945349.1	Q8IXF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP12A	ENST00000337801.9 link	c.277G>A	p.Glu93Lys	missense_variant	Exon 2 of 4	1	NM_198998.3	ENSP00000337144.4		Q8IXF9

Frequencies

GnomAD3 genomes

AF:

0.0000689

AC:

AN:

145088

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:

0.00190

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000503

GnomAD3 exomes

AF:

0.000100

AC:

AN:

239860

Hom.:

AF XY:

0.0000688

AC XY:

AN XY:

130730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000578

Gnomad SAS exome

AF:

0.0000674

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.000504

GnomAD4 exome

AF:

0.000100

AC:

144

AN:

1434168

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

713884

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00203

Gnomad4 SAS exome

AF:

0.0000239

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.0000536

Gnomad4 OTH exome

AF:

0.0000845

GnomAD4 genome

AF:

0.0000689

AC:

AN:

145174

Hom.:

Cov.:

AF XY:

0.0000848

AC XY:

AN XY:

70750

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00190

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000497

Alfa

AF:

0.0000964

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000847

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000597

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277G>A (p.E93K) alteration is located in exon 2 (coding exon 2) of the AQP12A gene. This alteration results from a G to A substitution at nucleotide position 277, causing the glutamic acid (E) at amino acid position 93 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

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.15

Sift

Benign

0.042

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;.

Vest4

0.20

MVP

0.34

MPC

0.46

ClinPred

0.10

GERP RS

2.6

Varity_R

0.053

gMVP

0.50

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