18-26861251-C-T

Variant names:

• chr18-26861251-C-T
• rs1839318
• NM_001650.7:c.492G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001650.7(AQP4):​c.492G>A​(p.Leu164Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,006 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (69 hom., cov: 33)
  • Exomes 𝑓: 0.023 (730 hom.)
• Consequence: AQP4 NM_001650.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 6 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=2.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

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.492G>A	p.Leu164Leu	synonymous	Exon 3 of 5	NP_001641.1	F1DSG4
	AQP4	NM_001317384.3		c.492G>A	p.Leu164Leu	synonymous	Exon 3 of 5	NP_001304313.1	A0A5F9ZHR4
	AQP4	NM_001364287.1		c.426G>A	p.Leu142Leu	synonymous	Exon 3 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.492G>A	p.Leu164Leu	synonymous	Exon 3 of 5	ENSP00000372654.4	P55087-1
	AQP4	ENST00000581374.5	TSL:1	c.426G>A	p.Leu142Leu	synonymous	Exon 2 of 4	ENSP00000462597.1	P55087-2
	AQP4	ENST00000672981.2		c.492G>A	p.Leu164Leu	synonymous	Exon 3 of 5	ENSP00000500598.2	A0A5F9ZHR4

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3753 AN: 152182 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0986

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0286 AC: 7180 AN: 251384 AF XY: 0.0329

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00899

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0232 AC: 33931 AN: 1461706 Hom.: 730 Cov.: 31 AF XY: 0.0255 AC XY: 18517 AN XY: 727160

African (AFR) AF: 0.0344 AC: 1151 AN: 33474

American (AMR) AF: 0.00903 AC: 404 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 579 AN: 26134

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39688

South Asian (SAS) AF: 0.0946 AC: 8157 AN: 86254

European-Finnish (FIN) AF: 0.0350 AC: 1870 AN: 53414

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5768

European-Non Finnish (NFE) AF: 0.0182 AC: 20237 AN: 1111858

Other (OTH) AF: 0.0208 AC: 1254 AN: 60394

GnomAD4 genome AF: 0.0246 AC: 3753 AN: 152300 Hom.: 69 Cov.: 33 AF XY: 0.0268 AC XY: 1993 AN XY: 74468

African (AFR) AF: 0.0330 AC: 1372 AN: 41566

American (AMR) AF: 0.0124 AC: 190 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5186

South Asian (SAS) AF: 0.0983 AC: 474 AN: 4822

European-Finnish (FIN) AF: 0.0360 AC: 382 AN: 10620

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0176 AC: 1197 AN: 68012

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0214 Hom.: 42

Bravo AF: 0.0216

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0186

EpiControl AF: 0.0175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1839318; hg19: chr18-24441215; COSMIC: COSV107497061; COSMIC: COSV107497061;