16-25217405-C-A

Position:

• chr16-25217405-C-A

Variant summary

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

The NM_001169.3(AQP8):​c.220C>A​(p.Leu74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 1.95

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.220C>A	p.Leu74Met	missense_variant	2/6	ENST00000219660.6	NP_001160.2
AQP8	XM_011545822.3	c.223C>A	p.Leu75Met	missense_variant	2/6		XP_011544124.1
AQP8	XM_011545823.3	c.223C>A	p.Leu75Met	missense_variant	2/4		XP_011544125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP8	ENST00000219660.6	c.220C>A	p.Leu74Met	missense_variant	2/6	1	NM_001169.3	ENSP00000219660.5
AQP8	ENST00000566125.5	c.202C>A	p.Leu68Met	missense_variant	2/6	1		ENSP00000454457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 27, 2022

The c.220C>A (p.L74M) alteration is located in exon 2 (coding exon 2) of the AQP8 gene. This alteration results from a C to A substitution at nucleotide position 220, causing the leucine (L) at amino acid position 74 to be replaced by a methionine (M). 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	0.22
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;T
Eigen	Benign	0.016
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	.;D
Vest4		0.48
MutPred		0.62		.;Gain of disorder (P = 0.4591);
MVP		0.79
MPC		0.70
ClinPred		0.83	D
GERP RS		2.4
Varity_R		0.12
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-25228726;