18-26862428-C-A

Variant names:

• chr18-26862428-C-A
• rs35248760
• NM_001650.7:c.201G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001650.7(AQP4):​c.201G>T​(p.Pro67Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,614,072 control chromosomes in the GnomAD database, including 11,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.087 (810 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10275 hom.)
• Consequence: AQP4 NM_001650.7 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.47
• Publications: 12 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 18-26862428-C-A is Benign according to our data. Variant chr18-26862428-C-A is described in ClinVar as Benign. ClinVar VariationId is 3060164.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP4	NM_001650.7	c.201G>T	p.Pro67Pro	synonymous_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.201G>T	p.Pro67Pro	synonymous_variant	Exon 2 of 5	1	NM_001650.7	ENSP00000372654.4

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13286 AN: 152070 Hom.: 810 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0943

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0941

GnomAD2 exomes AF: 0.0896 AC: 22519 AN: 251424 AF XY: 0.0899

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.0673

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.112 AC: 163222 AN: 1461884 Hom.: 10275 Cov.: 32 AF XY: 0.110 AC XY: 79750 AN XY: 727246

African (AFR) AF: 0.0177 AC: 592 AN: 33480

American (AMR) AF: 0.0682 AC: 3048 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3270 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0296 AC: 2552 AN: 86258

European-Finnish (FIN) AF: 0.146 AC: 7812 AN: 53420

Middle Eastern (MID) AF: 0.0794 AC: 458 AN: 5768

European-Non Finnish (NFE) AF: 0.125 AC: 139103 AN: 1112004

Other (OTH) AF: 0.106 AC: 6382 AN: 60394

GnomAD4 genome AF: 0.0873 AC: 13284 AN: 152188 Hom.: 810 Cov.: 32 AF XY: 0.0873 AC XY: 6490 AN XY: 74380

African (AFR) AF: 0.0223 AC: 926 AN: 41544

American (AMR) AF: 0.0942 AC: 1441 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0253 AC: 122 AN: 4826

European-Finnish (FIN) AF: 0.157 AC: 1658 AN: 10566

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.123 AC: 8336 AN: 67990

Other (OTH) AF: 0.0931 AC: 197 AN: 2116

Alfa AF: 0.0948 Hom.: 739

Bravo AF: 0.0802

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AQP4-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.036
DANN	Benign	0.79
PhyloP100		-1.5
PromoterAI		0.035	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35248760; hg19: chr18-24442392; COSMIC: COSV108231533; COSMIC: COSV108231533;