rs61753907

chr9-93308387-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006648.4(WNK2):c.6319G>A(p.Val2107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,573,848 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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: 𝑓 0.0051 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (45 hom.)
• Consequence: WNK2 NM_006648.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041105747).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00368 (5229/1421524) while in subpopulation SAS AF= 0.0189 (1525/80628). AF 95% confidence interval is 0.0181. There are 45 homozygotes in gnomad4_exome. There are 2998 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 775 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK2	NM_006648.4	c.6319G>A	p.Val2107Ile	missense_variant	28/30	ENST00000427277.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK2	ENST00000427277.7	c.6319G>A	p.Val2107Ile	missense_variant	28/30	5	NM_006648.4	A2

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 775 AN: 152206 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00975

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00505 AC: 955 AN: 189136 Hom.: 15 AF XY: 0.00622 AC XY: 629 AN XY: 101160

Gnomad AFR exome AF: 0.00893

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0000737

Gnomad SAS exome AF: 0.0194

Gnomad FIN exome AF: 0.000454

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00368 AC: 5229 AN: 1421524 Hom.: 45 Cov.: 31 AF XY: 0.00426 AC XY: 2998 AN XY: 703362

Gnomad4 AFR exome AF: 0.00929

Gnomad4 AMR exome AF: 0.00214

Gnomad4 ASJ exome AF: 0.00397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.000438

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00410

GnomAD4 genome AF: 0.00509 AC: 775 AN: 152324 Hom.: 4 Cov.: 33 AF XY: 0.00532 AC XY: 396 AN XY: 74494

Gnomad4 AFR AF: 0.00972

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0159

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00318

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00342 Hom.: 2

Bravo AF: 0.00501

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00775 AC: 34

ESP6500EA AF: 0.00385 AC: 33

ExAC AF: 0.00458 AC: 548

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.042	T;.
Eigen	Benign	-0.076
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.77	N;.
MutationTaster	Benign	0.96	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.038
Sift	Benign	0.23	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.68	P;B
Vest4		0.066
MVP		0.28
MPC		0.11
ClinPred		0.0079	T
GERP RS		3.6
Varity_R		0.051
gMVP		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61753907; hg19: chr9-96070669;