18-26862246-A-T

Variant names:

• chr18-26862246-A-T
• NM_001650.7:c.383T>A

Variant summary

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

The NM_001650.7(AQP4):​c.383T>A​(p.Ile128Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AQP4 NM_001650.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP4	NM_001650.7	c.383T>A	p.Ile128Asn	missense_variant	Exon 2 of 5	ENST00000383168.9	NP_001641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP4	ENST00000383168.9	c.383T>A	p.Ile128Asn	missense_variant	Exon 2 of 5	1	NM_001650.7	ENSP00000372654.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.;.;D
Eigen	Benign	0.042
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.9	M;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.4	N;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.012	D;.;.;.
Sift4G	Uncertain	0.019	D;D;D;.
Polyphen		0.68	P;.;.;.
Vest4		0.63
MutPred		0.74		Loss of stability (P = 0.0454);.;.;.;
MVP		0.91
MPC		0.23
ClinPred		0.89	D
GERP RS		4.4
Varity_R		0.24
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-24442210;