9-93230905-A-G

Position:

• chr9-93230905-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006648.4(WNK2):​c.872A>G​(p.Lys291Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WNK2 NM_006648.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK2	NM_006648.4	c.872A>G	p.Lys291Arg	missense_variant	4/30	ENST00000427277.7	NP_006639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK2	ENST00000427277.7	c.872A>G	p.Lys291Arg	missense_variant	4/30	5	NM_006648.4	ENSP00000411181	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.872A>G (p.K291R) alteration is located in exon 3 (coding exon 3) of the WNK2 gene. This alteration results from a A to G substitution at nucleotide position 872, causing the lysine (K) at amino acid position 291 to be replaced by an arginine (R). 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	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.82	.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.075	T;D;D
Sift4G	Benign	0.11	T;D;D
Polyphen		1.0	.;D;D
Vest4		0.14, 0.18
MutPred		0.55		Loss of methylation at K291 (P = 0.0059);Loss of methylation at K291 (P = 0.0059);Loss of methylation at K291 (P = 0.0059);
MVP		0.24
MPC		1.2
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.43
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr9-95993187;