chr9-93229721-G-A

Position:

• chr9-93229721-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006648.4(WNK2):​c.707G>A​(p.Arg236Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,461,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: WNK2 NM_006648.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

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.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK2	NM_006648.4	c.707G>A	p.Arg236Gln	missense_variant	3/30	ENST00000427277.7	NP_006639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK2	ENST00000427277.7	c.707G>A	p.Arg236Gln	missense_variant	3/30	5	NM_006648.4	ENSP00000411181	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461032 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726746

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jun 24, 2022

The c.707G>A (p.R236Q) alteration is located in exon 2 (coding exon 2) of the WNK2 gene. This alteration results from a G to A substitution at nucleotide position 707, causing the arginine (R) at amino acid position 236 to be replaced by a glutamine (Q). 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	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.3	.;L;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;D;D
REVEL	Benign	0.26
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.99, 0.99	.;D;D
Vest4		0.36, 0.30
MutPred		0.52		Gain of ubiquitination at K240 (P = 0.0444);Gain of ubiquitination at K240 (P = 0.0444);Gain of ubiquitination at K240 (P = 0.0444);
MVP		0.24
MPC		1.6
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.43
gMVP		0.92

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: rs968476403; hg19: chr9-95992003;