16-25224458-A-G

Position:

• chr16-25224458-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001169.3(AQP8):​c.484A>G​(p.Ile162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AQP8 NM_001169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.518

Genes affected

AQP8 (HGNC:642): (aquaporin 8) Aquaporin 8 (AQP8) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 8 mRNA is found in pancreas and colon but not other tissues. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06700319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP8	NM_001169.3	c.484A>G	p.Ile162Val	missense_variant	4/6	ENST00000219660.6	NP_001160.2
AQP8	XM_011545822.3	c.487A>G	p.Ile163Val	missense_variant	4/6		XP_011544124.1
AQP8	XM_011545823.3	c.264-2610A>G		intron_variant			XP_011544125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP8	ENST00000219660.6	c.484A>G	p.Ile162Val	missense_variant	4/6	1	NM_001169.3	ENSP00000219660.5
AQP8	ENST00000566125.5	c.466A>G	p.Ile156Val	missense_variant	4/6	1		ENSP00000454457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2022

The c.484A>G (p.I162V) alteration is located in exon 4 (coding exon 4) of the AQP8 gene. This alteration results from a A to G substitution at nucleotide position 484, causing the isoleucine (I) at amino acid position 162 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.071
DANN	Benign	0.27
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.66	.;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.17
Sift	Benign	0.80	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0	.;B
Vest4		0.053
MutPred		0.53		.;Gain of catalytic residue at I162 (P = 0.0026);
MVP		0.52
MPC		0.19
ClinPred		0.057	T
GERP RS		-4.4
Varity_R		0.024
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1567344547; hg19: chr16-25235779;