rs55781437

chr17-42787837-G-Achr17-42787837-G-T

Variant summary

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

The NM_032387.5(WNK4):c.1801G>A(p.Ala601Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A601S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WNK4 NM_032387.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18800458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK4	NM_032387.5	c.1801G>A	p.Ala601Thr	missense_variant	8/19	ENST00000246914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK4	ENST00000246914.10	c.1801G>A	p.Ala601Thr	missense_variant	8/19	1	NM_032387.5	P1
WNK4	ENST00000591448.5	c.*302G>A		3_prime_UTR_variant, NMD_transcript_variant	7/18	1
WNK4	ENST00000587705.5	n.422-293G>A		intron_variant, non_coding_transcript_variant		4
WNK4	ENST00000592072.1	n.422-293G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247274 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460138 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.089
Sift	Benign	0.055	T
Sift4G	Benign	0.14	T
Polyphen		0.61	P
Vest4		0.27
MutPred		0.14		Gain of glycosylation at A601 (P = 0.0031);
MVP		0.66
MPC		0.16
ClinPred		0.22	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.20

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: rs55781437; hg19: chr17-40939855;