17-42795306-G-C

Position:

• chr17-42795306-G-C

Variant summary

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

The NM_032387.5(WNK4):​c.2885G>C​(p.Ser962Thr) 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. 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: 31)
• Consequence: WNK4 NM_032387.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.583

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]

COA3 (HGNC:24990): (cytochrome c oxidase assembly factor 3) This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function. [provided by RefSeq, Nov 2012]

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=0.20944735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK4	NM_032387.5	c.2885G>C	p.Ser962Thr	missense_variant	14/19	ENST00000246914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK4	ENST00000246914.10	c.2885G>C	p.Ser962Thr	missense_variant	14/19	1	NM_032387.5	P1
WNK4	ENST00000591448.5	c.*1386G>C		3_prime_UTR_variant, NMD_transcript_variant	13/18	1
WNK4	ENST00000587745.1	c.71-319G>C		intron_variant		5
COA3	ENST00000586680.1	c.*990C>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

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

Jul 19, 2022

The c.2885G>C (p.S962T) alteration is located in exon 14 (coding exon 14) of the WNK4 gene. This alteration results from a G to C substitution at nucleotide position 2885, causing the serine (S) at amino acid position 962 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	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.66
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.11	T
Sift4G	Benign	0.41	T
Polyphen		0.96	P
Vest4		0.26
MutPred		0.25		Gain of glycosylation at S962 (P = 0.1993);
MVP		0.55
MPC		0.15
ClinPred		0.53	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr17-40947324;