X-54202076-C-T

Variant names:

• chrX-54202076-C-T
• ENST00000354646.7:c.4988G>A

Variant summary

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

The ENST00000354646.7(WNK3):​c.4988G>A​(p.Gly1663Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.43
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.4988G>A	p.Gly1663Glu	missense_variant	Exon 23 of 24		NP_065973.2
WNK3	NM_001002838.4	c.4817G>A	p.Gly1606Glu	missense_variant	Exon 22 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.4817G>A	p.Gly1606Glu	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.4988G>A	p.Gly1663Glu	missense_variant	Exon 23 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.4817G>A	p.Gly1606Glu	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 specified Uncertain:1

Mar 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4988G>A (p.G1663E) alteration is located in exon 23 (coding exon 22) of the WNK3 gene. This alteration results from a G to A substitution at nucleotide position 4988, causing the glycine (G) at amino acid position 1663 to be replaced by a glutamic acid (E). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	T;T;.;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.9	.;M;M;.
PhyloP100		6.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.1	D;D;D;.
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.52
MutPred		0.36		.;Gain of disorder (P = 0.0449);Gain of disorder (P = 0.0449);.;
MVP		0.58
MPC		0.93
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.89
gMVP		0.52
Mutation Taster		=96/4	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

hg19: chrX-54228509;