12-886025-A-G

Position:

chr12-886025-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_StrongBP6_Moderate

The NM_213655.5(WNK1):c.5977A>G(p.Thr1993Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000382 in 1,598,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1993I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

WNK1
NM_213655.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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 4.7 (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=0.013862491).

BP6

Variant 12-886025-A-G is Benign according to our data. Variant chr12-886025-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 568784.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5 linkuse as main transcript	c.5977A>G	p.Thr1993Ala	missense_variant	19/28	ENST00000340908.9
WNK1	NM_018979.4 linkuse as main transcript	c.5221A>G	p.Thr1741Ala	missense_variant	19/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9 linkuse as main transcript	c.5977A>G	p.Thr1993Ala	missense_variant	19/28	5	NM_213655.5	A2	Q9H4A3-5
WNK1	ENST00000315939.11 linkuse as main transcript	c.5221A>G	p.Thr1741Ala	missense_variant	19/28	1	NM_018979.4	P2	Q9H4A3-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

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

GnomAD3 exomes

AF:

0.0000721

AC:

AN:

235648

Hom.:

AF XY:

0.0000392

AC XY:

AN XY:

127440

show subpopulations

Gnomad AFR exome

AF:

0.000999

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000565

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1446472

Hom.:

Cov.:

AF XY:

0.00000834

AC XY:

AN XY:

719336

show subpopulations

Gnomad4 AFR exome

AF:

0.000646

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000243

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.24

DANN

Benign

0.24

DEOGEN2

Benign

0.069

T;.;T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.58

T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.66

.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.030

N;.;N;.;N

REVEL

Benign

0.070

Sift

Benign

0.67

T;.;T;.;T

Sift4G

Benign

0.99

T;.;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.037

MVP

0.082

MPC

0.12

ClinPred

0.0068

GERP RS

-5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.20

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over