NM_001650.7:c.366G>A

Variant names:

• chr18-26862263-C-T
• rs72557968
• NM_001650.7:c.366G>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.366G>A​(p.Gln122Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,614,164 control chromosomes in the GnomAD database, including 706 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 0.018 (44 hom., cov: 32)
  • Exomes 𝑓: 0.022 (662 hom.)
• Consequence: AQP4 NM_001650.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15
• 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=-0.35).
• BP7: Synonymous conserved (PhyloP=3.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0863 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.366G>A	p.Gln122Gln	synonymous	Exon 2 of 5	NP_001641.1	F1DSG4
	AQP4	NM_001317384.3		c.366G>A	p.Gln122Gln	synonymous	Exon 2 of 5	NP_001304313.1	A0A5F9ZHR4
	AQP4	NM_001364287.1		c.300G>A	p.Gln100Gln	synonymous	Exon 2 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.366G>A	p.Gln122Gln	synonymous	Exon 2 of 5	ENSP00000372654.4	P55087-1
	AQP4	ENST00000581374.5	TSL:1	c.300G>A	p.Gln100Gln	synonymous	Exon 1 of 4	ENSP00000462597.1	P55087-2
	AQP4	ENST00000672981.2		c.366G>A	p.Gln122Gln	synonymous	Exon 2 of 5	ENSP00000500598.2	A0A5F9ZHR4

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2736 AN: 152168 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00989

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.0938

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0263 AC: 6620 AN: 251376 AF XY: 0.0310

Gnomad AFR exome AF: 0.00979

Gnomad AMR exome AF: 0.00827

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0223 AC: 32615 AN: 1461878 Hom.: 662 Cov.: 31 AF XY: 0.0246 AC XY: 17875 AN XY: 727242

African (AFR) AF: 0.00938 AC: 314 AN: 33480

American (AMR) AF: 0.00823 AC: 368 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 579 AN: 26136

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39700

South Asian (SAS) AF: 0.0906 AC: 7817 AN: 86258

European-Finnish (FIN) AF: 0.0350 AC: 1871 AN: 53404

Middle Eastern (MID) AF: 0.0352 AC: 203 AN: 5768

European-Non Finnish (NFE) AF: 0.0182 AC: 20238 AN: 1112012

Other (OTH) AF: 0.0192 AC: 1158 AN: 60396

GnomAD4 genome AF: 0.0179 AC: 2733 AN: 152286 Hom.: 44 Cov.: 32 AF XY: 0.0205 AC XY: 1523 AN XY: 74450

African (AFR) AF: 0.00989 AC: 411 AN: 41562

American (AMR) AF: 0.0110 AC: 169 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5174

South Asian (SAS) AF: 0.0935 AC: 451 AN: 4826

European-Finnish (FIN) AF: 0.0358 AC: 380 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1193 AN: 68024

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0176 Hom.: 52

Bravo AF: 0.0139

Asia WGS AF: 0.0410 AC: 144 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0176

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		3.1
Mutation Taster		=96/4	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: rs72557968; hg19: chr18-24442227; COSMIC: COSV107497062; COSMIC: COSV107497062;