chr9-93184967-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_006648.4(WNK2):​c.38C>A​(p.Thr13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000461 in 1,084,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T13M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

WNK2
NM_006648.4 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.632
Variant links:
Genes affected
WNK2 (HGNC:14542): (WNK lysine deficient protein kinase 2) The protein encoded by this gene is a cytoplasmic serine-threonine kinase that belongs to the protein kinase superfamily. The protein plays an important role in the regulation of electrolyte homeostasis, cell signaling survival, and proliferation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10317221).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WNK2NM_006648.4 linkc.38C>A p.Thr13Lys missense_variant Exon 2 of 30 ENST00000427277.7 NP_006639.3 E9PCD1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WNK2ENST00000427277.7 linkc.38C>A p.Thr13Lys missense_variant Exon 2 of 30 5 NM_006648.4 ENSP00000411181.4 E9PCD1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000461
AC:
5
AN:
1084880
Hom.:
0
Cov.:
31
AF XY:
0.00000388
AC XY:
2
AN XY:
515594
show subpopulations
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:
0.00000541
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 17, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.T13K variant (also known as c.38C>A), located in coding exon 1 of the WNK2 gene, results from a C to A substitution at nucleotide position 38. The threonine at codon 13 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
23
DANN
Benign
0.92
DEOGEN2
Benign
0.062
.;T;.
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.87
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.64
T;T;T
M_CAP
Pathogenic
0.68
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.0
.;N;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.11
Sift
Uncertain
0.010
D;D;D
Sift4G
Benign
0.10
T;T;T
Polyphen
0.0
.;B;B
Vest4
0.083, 0.12
MutPred
0.19
Gain of ubiquitination at T13 (P = 0.0045);Gain of ubiquitination at T13 (P = 0.0045);Gain of ubiquitination at T13 (P = 0.0045);
MVP
0.068
MPC
1.7
ClinPred
0.081
T
GERP RS
0.86
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.077
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: chr9-95947249; API