X-54202065-T-G

Variant names:

• chrX-54202065-T-G
• rs782819287
• ENST00000354646.7:c.4999A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000354646.7(WNK3):​c.4999A>C​(p.Ile1667Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: WNK3 ENST00000354646.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.124
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05360049).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.4999A>C	p.Ile1667Leu	missense_variant	Exon 23 of 24		NP_065973.2
WNK3	NM_001002838.4	c.4828A>C	p.Ile1610Leu	missense_variant	Exon 22 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.4828A>C	p.Ile1610Leu	missense_variant	Exon 22 of 23		NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7	c.4999A>C	p.Ile1667Leu	missense_variant	Exon 23 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.4828A>C	p.Ile1610Leu	missense_variant	Exon 22 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 01, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.063	.;T;T;.
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.67	T;T;.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.054	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L;L;.
PhyloP100		0.12
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.36	N;N;N;.
REVEL	Benign	0.028
Sift	Benign	0.18	T;T;T;.
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0050	B;B;B;.
Vest4		0.17
MutPred		0.21		.;Gain of disorder (P = 0.035);Gain of disorder (P = 0.035);.;
MVP		0.11
MPC		0.21
ClinPred		0.048	T
GERP RS		1.3
Varity_R		0.13
gMVP		0.043
Mutation Taster		=97/3	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: rs782819287; hg19: chrX-54228498;