16-25217408-G-A

Position:

• chr16-25217408-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001169.3(AQP8):​c.223G>A​(p.Ala75Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AQP8 NM_001169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP8	NM_001169.3	c.223G>A	p.Ala75Thr	missense_variant	2/6	ENST00000219660.6	NP_001160.2
AQP8	XM_011545822.3	c.226G>A	p.Ala76Thr	missense_variant	2/6		XP_011544124.1
AQP8	XM_011545823.3	c.226G>A	p.Ala76Thr	missense_variant	2/4		XP_011544125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP8	ENST00000219660.6	c.223G>A	p.Ala75Thr	missense_variant	2/6	1	NM_001169.3	ENSP00000219660.5
AQP8	ENST00000566125.5	c.205G>A	p.Ala69Thr	missense_variant	2/6	1		ENSP00000454457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.00318 AC: 11 AN: 3478

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

Jan 30, 2024

The c.223G>A (p.A75T) alteration is located in exon 2 (coding exon 2) of the AQP8 gene. This alteration results from a G to A substitution at nucleotide position 223, causing the alanine (A) at amino acid position 75 to be replaced by a threonine (T). 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	0.23
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.5	.;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.24	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.68	.;P
Vest4		0.37
MutPred		0.70		.;Gain of helix (P = 0.2294);
MVP		0.92
MPC		0.38
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.096
gMVP		0.70

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: rs1022427921; hg19: chr16-25228729;