X-54202019-T-G

Variant names:

• chrX-54202019-T-G
• rs782342462
• ENST00000354646.7:c.5045A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000354646.7(WNK3):​c.5045A>C​(p.Glu1682Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,097,912 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
  • Failed GnomAD Quality Control
• Consequence: WNK3 ENST00000354646.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23222947).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.5045A>C	p.Glu1682Ala	missense_variant	Exon 23 of 24		NP_065973.2
WNK3	NM_001002838.4	c.4874A>C	p.Glu1625Ala	missense_variant	Exon 22 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.4874A>C	p.Glu1625Ala	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.5045A>C	p.Glu1682Ala	missense_variant	Exon 23 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.4874A>C	p.Glu1625Ala	missense_variant	Exon 22 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 112167 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183090 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1097912 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 363284

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000154 AC: 13 AN: 841892

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 112167 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34313

African (AFR) AF: 0.00 AC: 0 AN: 30883

American (AMR) AF: 0.00 AC: 0 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3593

South Asian (SAS) AF: 0.00 AC: 0 AN: 2703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53283

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.0000660 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5045A>C (p.E1682A) alteration is located in exon 23 (coding exon 22) of the WNK3 gene. This alteration results from a A to C substitution at nucleotide position 5045, causing the glutamic acid (E) at amino acid position 1682 to be replaced by an alanine (A). 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	0.22
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.0	.;M;M;.
PhyloP100		6.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D;D;D;.
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D;D;D;.
Sift4G	Benign	0.17	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.28
MutPred		0.20		.;Gain of helix (P = 0.027);Gain of helix (P = 0.027);.;
MVP		0.25
MPC		0.47
ClinPred		0.81	D
GERP RS		4.9
Varity_R		0.38
gMVP		0.31
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: rs782342462; hg19: chrX-54228452;