X-54202086-C-A

Variant names:

• chrX-54202086-C-A
• ENST00000354646.7:c.4978G>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Moderate PP5_Moderate

The ENST00000354646.7(WNK3):​c.4978G>T​(p.Glu1660*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: WNK3 ENST00000354646.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.78
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-54202086-C-A is Pathogenic according to our data. Variant chrX-54202086-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3774998.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.4978G>T	p.Glu1660*	stop_gained	Exon 23 of 24		NP_065973.2
WNK3	NM_001002838.4	c.4807G>T	p.Glu1603*	stop_gained	Exon 22 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.4807G>T	p.Glu1603*	stop_gained	Exon 22 of 23		NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7	c.4978G>T	p.Glu1660*	stop_gained	Exon 23 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.4807G>T	p.Glu1603*	stop_gained	Exon 22 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	46
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		4.8
Vest4		0.75
GERP RS		4.9
Mutation Taster		=18/182	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-54228519; COSMIC: COSV100672444;