12-49962352-A-G

Position:

chr12-49962352-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001651.4(AQP5):c.335A>G(p.Asn112Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000652 in 1,594,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

AQP5
NM_001651.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10

Variant links:

Genes affected

AQP5 (HGNC:638): (aquaporin 5) Aquaporin 5 (AQP5) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 5 plays a role in the generation of saliva, tears and pulmonary secretions. AQP0, AQP2, AQP5, and AQP6 are closely related and all map to 12q13. [provided by RefSeq, Jul 2008]

AQP5 links:

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

AQP5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.085336745).

BS2

High AC in GnomAdExome4 at 101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP5	NM_001651.4 linkuse as main transcript	c.335A>G	p.Asn112Ser	missense_variant	1/4	ENST00000293599.7	NP_001642.1
AQP5-AS1	NR_110591.1 linkuse as main transcript	n.117+315T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
AQP5	ENST00000293599.7 linkuse as main transcript	c.335A>G	p.Asn112Ser	missense_variant	1/4	1	NM_001651.4	ENSP00000293599	P1
AQP5-AS1	ENST00000550530.1 linkuse as main transcript	n.117+315T>C		intron_variant, non_coding_transcript_variant		3
AQP5-AS1	ENST00000550214.1 linkuse as main transcript	n.258+315T>C		intron_variant, non_coding_transcript_variant		2
AQP5-AS1	ENST00000552379.1 linkuse as main transcript	n.256+315T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150332

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000498

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000204

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000891

AC:

AN:

235600

Hom.:

AF XY:

0.0000851

AC XY:

AN XY:

129284

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000398

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.0000699

AC:

101

AN:

1444084

Hom.:

Cov.:

AF XY:

0.0000849

AC XY:

AN XY:

718724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000455

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000296

Gnomad4 SAS exome

AF:

0.0000816

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000721

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000200

AC:

AN:

150332

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73490

show subpopulations

Gnomad4 AFR

AF:

0.0000498

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000204

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000909

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AQP5 protein function. ClinVar contains an entry for this variant (Variation ID: 1474842). This variant has not been reported in the literature in individuals affected with AQP5-related conditions. This variant is present in population databases (rs755928749, gnomAD 0.04%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 112 of the AQP5 protein (p.Asn112Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.72

M_CAP

Benign

0.055

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.19

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

REVEL

Benign

0.17

Sift

Benign

0.86

Sift4G

Benign

0.74

Polyphen

0.0010

Vest4

0.24

MVP

0.85

MPC

0.29

ClinPred

0.019

GERP RS

3.7

Varity_R

0.31

gMVP

0.36

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