Genetic Variant AQP12A:p.Gly77Arg (chr2-240692179-G-C) – 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_198998.3(AQP12A):c.229G>C(p.Gly77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,444 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

AQP12A
NM_198998.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

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:

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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, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP12A	NM_198998.3 link	c.229G>C	p.Gly77Arg	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.229G>C	p.Gly77Arg	missense_variant	Exon 2 of 4	1	NM_198998.3	ENSP00000337144.4		Q8IXF9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000415

AC:

AN:

241090

Hom.:

AF XY:

0.00000762

AC XY:

AN XY:

131292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

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:

0.00000348

AC:

AN:

1437444

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

715426

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000272

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229G>C (p.G77R) alteration is located in exon 2 (coding exon 2) of the AQP12A gene. This alteration results from a G to C substitution at nucleotide position 229, causing the glycine (G) at amino acid position 77 to be replaced by an arginine (R). 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

0.21

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.75

T;T

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

1.0

D;.

Vest4

0.52

MutPred

0.90

Gain of loop (P = 0.1069);.;

MVP

0.80

MPC

0.70

ClinPred

0.91

GERP RS

2.6

Varity_R

0.31

gMVP

0.81

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