17-42780715-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032387.5(WNK4):​c.17C>A​(p.Ala6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

WNK4
NM_032387.5 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.320
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.16835317).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WNK4NM_032387.5 linkuse as main transcriptc.17C>A p.Ala6Asp missense_variant 1/19 ENST00000246914.10 NP_115763.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNK4ENST00000246914.10 linkuse as main transcriptc.17C>A p.Ala6Asp missense_variant 1/191 NM_032387.5 ENSP00000246914 P1Q96J92-1
WNK4ENST00000591448.5 linkuse as main transcriptc.17C>A p.Ala6Asp missense_variant, NMD_transcript_variant 1/181 ENSP00000467088

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00000423
AC:
1
AN:
236210
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
130000
show subpopulations
Gnomad AFR exome
AF:
0.0000692
Gnomad AMR exome
AF:
0.00
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
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1456452
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
724754
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000657
AC:
1
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
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
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 11, 2021The c.17C>A (p.A6D) alteration is located in exon 1 (coding exon 1) of the WNK4 gene. This alteration results from a C to A substitution at nucleotide position 17, causing the alanine (A) at amino acid position 6 to be replaced by an aspartic acid (D). 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
0.12
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
16
DANN
Benign
0.93
DEOGEN2
Benign
0.27
T
Eigen
Benign
-0.96
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.67
T
M_CAP
Pathogenic
0.40
D
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.7
D
REVEL
Benign
0.10
Sift
Uncertain
0.018
D
Sift4G
Benign
0.11
T
Polyphen
0.019
B
Vest4
0.29
MutPred
0.065
Loss of glycosylation at T7 (P = 0.1205);
MVP
0.45
MPC
0.97
ClinPred
0.046
T
GERP RS
1.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.23
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1209583360; hg19: chr17-40932733; API