Genetic Variant WNK3:p.Asn1624Ser (chrX-54202193-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000354646.7(WNK3):c.4871A>G(p.Asn1624Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000093 in 1,074,709 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1624I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

WNK3
ENST00000354646.7 missense, splice_region

Scores

Splicing: ADA: 0.00009678

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.33

Publications

0 publications found

Variant links:

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

WNK3 links:

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ACMG classification

Classification was made for transcript

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 (REVEL=0.03).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
WNK3	NM_020922.5 link	c.4871A>G	p.Asn1624Ser	missense_variant, splice_region_variant	Exon 23 of 24	NP_065973.2	Q9BYP7-1
WNK3	NM_001002838.4 link	c.4700A>G	p.Asp1567Gly	missense_variant, splice_region_variant	Exon 22 of 23	NP_001002838.1	Q9BYP7-3
WNK3	NM_001395166.1 link	c.4700A>G	p.Asp1567Gly	missense_variant, splice_region_variant	Exon 22 of 23	NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7 link	c.4871A>G	p.Asn1624Ser	missense_variant, splice_region_variant	Exon 23 of 24	1		ENSP00000346667.2		Q9BYP7-1
WNK3	ENST00000375169.7 link	c.4700A>G	p.Asp1567Gly	missense_variant, splice_region_variant	Exon 22 of 23	5		ENSP00000364312.3		Q9BYP7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.30e-7

AC:

AN:

1074709

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

344477

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25830

American (AMR)

AF:

0.00

AC:

AN:

31941

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18886

East Asian (EAS)

AF:

0.00

AC:

AN:

29875

South Asian (SAS)

AF:

0.00

AC:

AN:

50532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39759

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4056

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

828659

Other (OTH)

AF:

0.00

AC:

AN:

45171

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.71

FATHMM_MKL

Uncertain

0.88

M_CAP

Benign

0.0050

PhyloP100

2.3

ClinPred

0.17

GERP RS

3.7

Varity_R

0.075

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000097

dbscSNV1_RF

Benign

0.0020

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

Publications

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X-54202193-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over