rs200621254

Variant names:

• chrX-54198398-G-A
• rs200621254
• ENST00000354646.7:c.5329C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000354646.7(WNK3):​c.5329C>T​(p.Pro1777Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,208,904 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000097 (0 hom. 40 hem.)
• Consequence: WNK3 ENST00000354646.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20
• Publications: 3 publications found

Genes affected

WNK3 (HGNC:14543): (WNK lysine deficient protein kinase 3) This gene encodes a protein belonging to the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

WNK3 Gene-Disease associations (from GenCC):

• Prieto syndrome

  Inheritance: XL Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06356835).
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.5329C>T	p.Pro1777Ser	missense_variant	Exon 24 of 24		NP_065973.2
WNK3	NM_001002838.4	c.5158C>T	p.Pro1720Ser	missense_variant	Exon 23 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.5158C>T	p.Pro1720Ser	missense_variant	Exon 23 of 23		NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7	c.5329C>T	p.Pro1777Ser	missense_variant	Exon 24 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.5158C>T	p.Pro1720Ser	missense_variant	Exon 23 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes AF: 0.0000896 AC: 10 AN: 111663 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000132 AC: 24 AN: 181798 AF XY: 0.000196

Gnomad AFR exome AF: 0.0000764

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000724

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.0000966 AC: 106 AN: 1097186 Hom.: 0 Cov.: 30 AF XY: 0.000110 AC XY: 40 AN XY: 362596

African (AFR) AF: 0.0000379 AC: 1 AN: 26385

American (AMR) AF: 0.0000569 AC: 2 AN: 35146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30181

South Asian (SAS) AF: 0.000372 AC: 20 AN: 53792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40507

Middle Eastern (MID) AF: 0.00266 AC: 11 AN: 4134

European-Non Finnish (NFE) AF: 0.0000689 AC: 58 AN: 841606

Other (OTH) AF: 0.000282 AC: 13 AN: 46067

GnomAD4 genome AF: 0.0000895 AC: 10 AN: 111718 Hom.: 0 Cov.: 22 AF XY: 0.0000885 AC XY: 3 AN XY: 33900

African (AFR) AF: 0.000130 AC: 4 AN: 30798

American (AMR) AF: 0.00 AC: 0 AN: 10467

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.000379 AC: 1 AN: 2639

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6024

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53170

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000165

EpiControl AF: 0.000239

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5329C>T (p.P1777S) alteration is located in exon 24 (coding exon 23) of the WNK3 gene. This alteration results from a C to T substitution at nucleotide position 5329, causing the proline (P) at amino acid position 1777 to be replaced by a serine (S). 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	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;T;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.66	T;T;.;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;L;.
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.2	D;D;D;.
REVEL	Benign	0.078
Sift	Uncertain	0.0060	D;D;D;.
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		0.87	P;P;P;.
Vest4		0.16
MutPred		0.24		.;Gain of glycosylation at P1777 (P = 0.0135);Gain of glycosylation at P1777 (P = 0.0135);.;
MVP		0.11
MPC		0.22
ClinPred		0.075	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.39
Mutation Taster		=91/9	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: rs200621254; hg19: chrX-54224831;