NM_006648.4:c.133A>T

Variant names:

• chr9-93185062-A-T
• rs755723935
• NM_006648.4:c.133A>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_006648.4(WNK2):​c.133A>T​(p.Ser45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,153,276 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: WNK2 NM_006648.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310

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]

ACMG classification

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=0.1880405).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK2	NM_006648.4	c.133A>T	p.Ser45Cys	missense_variant	Exon 2 of 30	ENST00000427277.7	NP_006639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK2	ENST00000427277.7	c.133A>T	p.Ser45Cys	missense_variant	Exon 2 of 30	5	NM_006648.4	ENSP00000411181.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000706 AC: 3 AN: 42480 Hom.: 0 AF XY: 0.000114 AC XY: 3 AN XY: 26418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000434 AC: 5 AN: 1153276 Hom.: 0 Cov.: 31 AF XY: 0.00000890 AC XY: 5 AN XY: 561726

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: 0.000115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.000157 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.29	.;T;.
Eigen	Benign	0.031
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	2.0	.;M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.5	N;D;N
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.17, 0.31
MutPred		0.28		Loss of phosphorylation at S45 (P = 0.0017);Loss of phosphorylation at S45 (P = 0.0017);Loss of phosphorylation at S45 (P = 0.0017);
MVP		0.12
MPC		1.6
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.21
gMVP		0.54

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: rs755723935; hg19: chr9-95947344;