17-42780838-C-T

Position:

• chr17-42780838-C-T

Variant summary

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

The NM_032387.5(WNK4):​c.140C>T​(p.Ser47Phe) 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: WNK4 NM_032387.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.389

Genes affected

WNK4 (HGNC:14544): (WNK lysine deficient protein kinase 4) This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

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
WNK4	NM_032387.5	c.140C>T	p.Ser47Phe	missense_variant	1/19	ENST00000246914.10	NP_115763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK4	ENST00000246914.10	c.140C>T	p.Ser47Phe	missense_variant	1/19	1	NM_032387.5	ENSP00000246914	P1
WNK4	ENST00000591448.5	c.140C>T	p.Ser47Phe	missense_variant, NMD_transcript_variant	1/18	1		ENSP00000467088

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.140C>T (p.S47F) alteration is located in exon 1 (coding exon 1) of the WNK4 gene. This alteration results from a C to T substitution at nucleotide position 140, causing the serine (S) at amino acid position 47 to be replaced by a phenylalanine (F). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.92	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.077	T
Polyphen		0.99	D
Vest4		0.46
MutPred		0.24		Loss of phosphorylation at S47 (P = 7e-04);
MVP		0.68
MPC		0.71
ClinPred		0.95	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.29

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: chr17-40932856;