rs914392824

Variant names:

• chrX-54198544-G-A
• rs914392824
• ENST00000354646.7:c.5183C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000354646.7(WNK3):​c.5183C>T​(p.Pro1728Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: WNK3 ENST00000354646.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20489123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.5183C>T	p.Pro1728Leu	missense_variant	Exon 24 of 24		NP_065973.2
WNK3	NM_001002838.4	c.5012C>T	p.Pro1671Leu	missense_variant	Exon 23 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.5012C>T	p.Pro1671Leu	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.5183C>T	p.Pro1728Leu	missense_variant	Exon 24 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.5012C>T	p.Pro1671Leu	missense_variant	Exon 23 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5183C>T (p.P1728L) 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 5183, causing the proline (P) at amino acid position 1728 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;T;T;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T;T;.;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	.;M;M;.
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.1	D;D;D;.
REVEL	Benign	0.051
Sift	Uncertain	0.0040	D;D;D;.
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		0.51	P;B;B;.
Vest4		0.38
MutPred		0.28		.;Loss of disorder (P = 0.0207);Loss of disorder (P = 0.0207);.;
MVP		0.14
MPC		0.24
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.26
gMVP		0.30
Mutation Taster		=98/2	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: rs914392824; hg19: chrX-54224977;