NM_006648.4:c.67C>T

Variant names:

• chr9-93184996-C-T
• rs1371549502
• NM_006648.4:c.67C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006648.4(WNK2):​c.67C>T​(p.Pro23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,242,942 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. 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. P23T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: WNK2 NM_006648.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04607472).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006648.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK2	NM_006648.4	MANE Select	c.67C>T	p.Pro23Ser	missense	Exon 2 of 30	NP_006639.3
	WNK2	NM_001282394.3		c.67C>T	p.Pro23Ser	missense	Exon 2 of 31	NP_001269323.1	Q9Y3S1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK2	ENST00000427277.7	TSL:5 MANE Select	c.67C>T	p.Pro23Ser	missense	Exon 2 of 30	ENSP00000411181.4	E9PCD1
	WNK2	ENST00000297954.9	TSL:1	c.67C>T	p.Pro23Ser	missense	Exon 2 of 31	ENSP00000297954.4	Q9Y3S1-1
	WNK2	ENST00000432730.6	TSL:1	c.67C>T	p.Pro23Ser	missense	Exon 1 of 29	ENSP00000415038.2	Q9Y3S1-2

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1093170 Hom.: 0 Cov.: 31 AF XY: 0.00000383 AC XY: 2 AN XY: 522106

African (AFR) AF: 0.00 AC: 0 AN: 22504

American (AMR) AF: 0.00 AC: 0 AN: 8100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13884

East Asian (EAS) AF: 0.00 AC: 0 AN: 25916

South Asian (SAS) AF: 0.00 AC: 0 AN: 23060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2902

European-Non Finnish (NFE) AF: 0.00000322 AC: 3 AN: 931540

Other (OTH) AF: 0.00 AC: 0 AN: 43614

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149772 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73164

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40768

American (AMR) AF: 0.00 AC: 0 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4948

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67160

Other (OTH) AF: 0.00 AC: 0 AN: 2050

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		-1.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.068
Sift	Benign	0.66	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.039
MutPred		0.24		Gain of phosphorylation at P23 (P = 0.0166)
MVP		0.13
MPC		1.4
ClinPred		0.037	T
GERP RS		-3.4
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.029
gMVP		0.47
Mutation Taster		=293/7	polymorphism

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

Other links and lift over

dbSNP: rs1371549502; hg19: chr9-95947278;