18-26856296-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001650.7(AQP4):c.887C>G(p.Pro296Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: AQP4 NM_001650.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

Genes affected

AQP4 (HGNC:637): (aquaporin 4) This gene encodes a member of the aquaporin family of intrinsic membrane proteins that function as water-selective channels in the plasma membranes of many cells. This protein is the predominant aquaporin found in brain and has an important role in brain water homeostasis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. Additional isoforms, resulting from the use of alternative in-frame translation initiation codons, have also been described. Recent studies provided evidence for translational readthrough in this gene, and expression of C-terminally extended isoforms via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018]

AQP4-AS1 (HGNC:26399): (AQP4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23975855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7	c.887C>G	p.Pro296Arg	missense_variant	5/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.887C>G	p.Pro296Arg	missense_variant	5/5	1	NM_001650.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251480 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.887C>G (p.P296R) alteration is located in exon 5 (coding exon 5) of the AQP4 gene. This alteration results from a C to G substitution at nucleotide position 887, causing the proline (P) at amino acid position 296 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	0.18
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.8	N;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.038	D;.;.
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.33	B;.;.
Vest4		0.42
MutPred		0.34		Gain of sheet (P = 0.0266);.;.;
MVP		0.95
MPC		0.28
ClinPred		0.24	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs768757331; hg19: chr18-24436260;