Variant 12-754143-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_018979.4(WNK1):c.578C>T(p.Pro193Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

WNK1
NM_018979.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.601

Variant links:

Genes affected

WNK1 (HGNC:14540): (WNK lysine deficient protein kinase 1) This gene encodes a member of the WNK subfamily of serine/threonine protein kinases. The encoded protein may be a key regulator of blood pressure by controlling the transport of sodium and chloride ions. Mutations in this gene have been associated with pseudohypoaldosteronism type II and hereditary sensory neuropathy type II. Alternatively spliced transcript variants encoding different isoforms have been described but the full-length nature of all of them has yet to be determined.[provided by RefSeq, May 2010]

WNK1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WNK1. . Gene score misZ 2.1626 (greater than the threshold 3.09). Trascript score misZ 4.652 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory and autonomic, type 2A, hereditary sensory and autonomic neuropathy type 2, pseudohypoaldosteronism type 2C.

BP4

Computational evidence support a benign effect (MetaRNN=0.04692459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.578C>T	p.Pro193Leu	missense_variant	1/28	ENST00000340908.9	NP_998820.3	Q9H4A3-5
WNK1	NM_018979.4 linkuse as main transcript	c.578C>T	p.Pro193Leu	missense_variant	1/28	ENST00000315939.11	NP_061852.3	Q9H4A3-1A5D8Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9 linkuse as main transcript	c.578C>T	p.Pro193Leu	missense_variant	1/28	5	NM_213655.5	ENSP00000341292.5		Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.578C>T	p.Pro193Leu	missense_variant	1/28	1	NM_018979.4	ENSP00000313059.6		Q9H4A3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247518

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134700

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460426

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726484

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.25

T;.;D;.;.;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.047

T;T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.7

.;L;L;L;L;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.3

D;D;D;.;D;D

REVEL

Benign

0.11

Sift

Benign

0.14

T;T;T;.;T;T

Sift4G

Benign

0.31

T;.;T;T;T;T

Polyphen

0.0

B;.;B;.;.;B

Vest4

0.079

MutPred

0.18

Gain of stability (P = 0.1144);Gain of stability (P = 0.1144);Gain of stability (P = 0.1144);Gain of stability (P = 0.1144);Gain of stability (P = 0.1144);Gain of stability (P = 0.1144);

MVP

0.10

MPC

0.75

ClinPred

0.050

GERP RS

3.4

Varity_R

0.13

gMVP

0.19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over