Genetic Variant AQP12A:p.Met117Thr (chr2-240692300-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198998.3(AQP12A):c.350T>C(p.Met117Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 140,566 control chromosomes in the GnomAD database, including 1,144 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M117I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.042 ( 1144 hom., cov: 29)

Exomes 𝑓: 0.0057 ( 2174 hom. )

Failed GnomAD Quality Control

Consequence

AQP12A
NM_198998.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031016767).

BP6

Variant 2-240692300-T-C is Benign according to our data. Variant chr2-240692300-T-C is described in ClinVar as [Benign]. Clinvar id is 1286215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP12A	NM_198998.3 link	c.350T>C	p.Met117Thr	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.350T>C	p.Met117Thr	missense_variant	Exon 2 of 4	1	NM_198998.3	ENSP00000337144.4		Q8IXF9

Frequencies

GnomAD3 genomes

AF:

0.0415

AC:

5829

AN:

140478

Hom.:

1136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.000304

Gnomad EAS

AF:

0.00707

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.000193

Gnomad MID

AF:

0.0103

Gnomad NFE

AF:

0.00124

Gnomad OTH

AF:

0.0300

GnomAD3 exomes

AF:

0.0102

AC:

2388

AN:

235074

Hom.:

522

AF XY:

0.00820

AC XY:

1056

AN XY:

128730

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.000715

Gnomad EAS exome

AF:

0.00606

Gnomad SAS exome

AF:

0.00211

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.000681

Gnomad OTH exome

AF:

0.00617

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00572

AC:

8140

AN:

1421992

Hom.:

2174

Cov.:

AF XY:

0.00537

AC XY:

3803

AN XY:

707616

show subpopulations

Gnomad4 AFR exome

AF:

0.167

Gnomad4 AMR exome

AF:

0.0166

Gnomad4 ASJ exome

AF:

0.00303

Gnomad4 EAS exome

AF:

0.0154

Gnomad4 SAS exome

AF:

0.00601

Gnomad4 FIN exome

AF:

0.000213

Gnomad4 NFE exome

AF:

0.000661

Gnomad4 OTH exome

AF:

0.0118

GnomAD4 genome

AF:

0.0416

AC:

5850

AN:

140566

Hom.:

1144

Cov.:

AF XY:

0.0411

AC XY:

2818

AN XY:

68526

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.0159

Gnomad4 ASJ

AF:

0.000304

Gnomad4 EAS

AF:

0.00707

Gnomad4 SAS

AF:

0.00433

Gnomad4 FIN

AF:

0.000193

Gnomad4 NFE

AF:

0.00124

Gnomad4 OTH

AF:

0.0296

Alfa

AF:

0.0265

Hom.:

150

ESP6500AA

AF:

0.0773

AC:

321

ESP6500EA

AF:

0.000588

AC:

ExAC

AF:

0.0126

AC:

1481

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.8

DANN

Benign

0.31

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00085

LIST_S2

Benign

0.067

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.4

N;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

1.3

N;N

REVEL

Benign

0.045

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.072

MPC

0.39

ClinPred

0.00023

GERP RS

1.6

Varity_R

0.023

gMVP

0.37

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