9-93185161-C-T

Variant summary

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

The NM_006648.4(WNK2):​c.232C>T​(p.Leu78Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000398 in 1,255,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)
Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

WNK2
NM_006648.4 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.35
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]

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=0.12254229).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WNK2NM_006648.4 linkuse as main transcriptc.232C>T p.Leu78Phe missense_variant 2/30 ENST00000427277.7 NP_006639.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNK2ENST00000427277.7 linkuse as main transcriptc.232C>T p.Leu78Phe missense_variant 2/305 NM_006648.4 ENSP00000411181 A2

Frequencies

GnomAD3 genomes
AF:
0.0000267
AC:
4
AN:
149784
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000729
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000664
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
GnomAD4 exome
AF:
9.04e-7
AC:
1
AN:
1106194
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
535882
show subpopulations
Gnomad4 AFR exome
AF:
0.0000458
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:
0.0000267
AC:
4
AN:
149784
Hom.:
0
Cov.:
32
AF XY:
0.0000411
AC XY:
3
AN XY:
73074
show subpopulations
Gnomad4 AFR
AF:
0.0000729
Gnomad4 AMR
AF:
0.0000664
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
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2022The c.232C>T (p.L78F) alteration is located in exon 1 (coding exon 1) of the WNK2 gene. This alteration results from a C to T substitution at nucleotide position 232, causing the leucine (L) at amino acid position 78 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
Benign
0.27
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.054
.;T;.
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.064
N
LIST_S2
Benign
0.60
T;T;T
M_CAP
Pathogenic
0.71
D
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
.;M;.
MutationTaster
Benign
1.0
D;D;D;N;N
PrimateAI
Pathogenic
0.95
D
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.027
Sift
Uncertain
0.011
D;D;D
Sift4G
Benign
0.74
T;T;T
Polyphen
0.0050, 0.0090
.;B;B
Vest4
0.12, 0.14
MutPred
0.31
Loss of MoRF binding (P = 0.1365);Loss of MoRF binding (P = 0.1365);Loss of MoRF binding (P = 0.1365);
MVP
0.043
MPC
1.5
ClinPred
0.41
T
GERP RS
2.5
Varity_R
0.22
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: rs967634460; hg19: chr9-95947443; API