9-93308387-G-A

Variant names:

• chr9-93308387-G-A
• rs61753907
• NM_006648.4:c.6319G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2107A) has been classified as Uncertain significance.

• 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
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041105747).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 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 GnomAdExome4. There are 2998 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 775 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK2	NM_006648.4	MANE Select	c.6319G>A	p.Val2107Ile	missense	Exon 28 of 30	NP_006639.3
	WNK2	NM_001282394.3		c.6430G>A	p.Val2144Ile	missense	Exon 29 of 31	NP_001269323.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK2	ENST00000427277.7	TSL:5 MANE Select	c.6319G>A	p.Val2107Ile	missense	Exon 28 of 30	ENSP00000411181.4
	WNK2	ENST00000297954.9	TSL:1	c.6430G>A	p.Val2144Ile	missense	Exon 29 of 31	ENSP00000297954.4
	WNK2	ENST00000432730.6	TSL:1	c.6319G>A	p.Val2107Ile	missense	Exon 27 of 29	ENSP00000415038.2

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

GnomAD2 exomes AF: 0.00505 AC: 955 AN: 189136 AF XY: 0.00622

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 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

African (AFR) AF: 0.00929 AC: 302 AN: 32510

American (AMR) AF: 0.00214 AC: 82 AN: 38340

Ashkenazi Jewish (ASJ) AF: 0.00397 AC: 101 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 37242

South Asian (SAS) AF: 0.0189 AC: 1525 AN: 80628

European-Finnish (FIN) AF: 0.000438 AC: 22 AN: 50234

Middle Eastern (MID) AF: 0.0181 AC: 104 AN: 5732

European-Non Finnish (NFE) AF: 0.00261 AC: 2851 AN: 1092392

Other (OTH) AF: 0.00410 AC: 242 AN: 59010

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

African (AFR) AF: 0.00972 AC: 404 AN: 41572

American (AMR) AF: 0.00222 AC: 34 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0159 AC: 77 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68022

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00342 Hom.: 3

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 v4.9

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
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.77	N
PhyloP100		3.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.038
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.68	P
Vest4		0.066
MVP		0.28
MPC		0.11
ClinPred		0.0079	T
GERP RS		3.6
Varity_R		0.051
gMVP		0.075
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61753907; hg19: chr9-96070669; COSMIC: COSV107399470; COSMIC: COSV107399470;