NM_001650.7:c.887C>T

Variant names:

• chr18-26856296-G-A
• rs768757331
• NM_001650.7:c.887C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001650.7(AQP4):​c.887C>T​(p.Pro296Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P296R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AQP4 NM_001650.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.24
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31907243).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001650.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	NM_001650.7	MANE Select	c.887C>T	p.Pro296Leu	missense	Exon 5 of 5	NP_001641.1	F1DSG4
	AQP4	NM_001317384.3		c.887C>T	p.Pro296Leu	missense	Exon 5 of 5	NP_001304313.1	A0A5F9ZHR4
	AQP4	NM_001364287.1		c.821C>T	p.Pro274Leu	missense	Exon 5 of 5	NP_001351216.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	ENST00000383168.9	TSL:1 MANE Select	c.887C>T	p.Pro296Leu	missense	Exon 5 of 5	ENSP00000372654.4	P55087-1
	AQP4	ENST00000581374.5	TSL:1	c.821C>T	p.Pro274Leu	missense	Exon 4 of 4	ENSP00000462597.1	P55087-2
	AQP4	ENST00000672981.2		c.887C>T	p.Pro296Leu	missense	Exon 5 of 5	ENSP00000500598.2	A0A5F9ZHR4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.085	T
Sift4G	Benign	0.12	T
Polyphen		0.84	P
Vest4		0.37
MutPred		0.47		Gain of sheet (P = 0.0011)
MVP		0.95
MPC		0.22
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.11
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768757331; hg19: chr18-24436260;