16-25224381-G-C

Position:

• chr16-25224381-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001169.3(AQP8):​c.407G>C​(p.Arg136Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: AQP8 NM_001169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.220

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12319973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP8	NM_001169.3	c.407G>C	p.Arg136Thr	missense_variant	4/6	ENST00000219660.6	NP_001160.2
AQP8	XM_011545822.3	c.410G>C	p.Arg137Thr	missense_variant	4/6		XP_011544124.1
AQP8	XM_011545823.3	c.264-2687G>C		intron_variant			XP_011544125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP8	ENST00000219660.6	c.407G>C	p.Arg136Thr	missense_variant	4/6	1	NM_001169.3	ENSP00000219660.5
AQP8	ENST00000566125.5	c.389G>C	p.Arg130Thr	missense_variant	4/6	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

Mar 25, 2024

The c.407G>C (p.R136T) alteration is located in exon 4 (coding exon 4) of the AQP8 gene. This alteration results from a G to C substitution at nucleotide position 407, causing the arginine (R) at amino acid position 136 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	0.15
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Benign	0.22
DEOGEN2	Benign	0.18	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.81	.;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.23
Sift	Benign	0.61	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.033	.;B
Vest4		0.49
MutPred		0.36		.;Gain of glycosylation at R136 (P = 0.0645);
MVP		0.58
MPC		0.34
ClinPred		0.038	T
GERP RS		2.2
Varity_R		0.044
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr16-25235702;