rs956868

chr12-881746-A-Cchr12-881746-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_213655.5(WNK1):c.3922A>C(p.Thr1308Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,940 control chromosomes in the GnomAD database, including 575,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1308T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.84 (53881 hom., cov: 31)
  • Exomes 𝑓: 0.84 (521657 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0690

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, WNK1
• BP4: Computational evidence support a benign effect (MetaRNN=7.2372313E-7).
• BP6: Variant 12-881746-A-C is Benign according to our data. Variant chr12-881746-A-C is described in ClinVar as [Benign]. Clinvar id is 261070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-881746-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.3922A>C	p.Thr1308Pro	missense_variant	13/28	ENST00000340908.9
WNK1	NM_018979.4	c.3166A>C	p.Thr1056Pro	missense_variant	13/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.3922A>C	p.Thr1308Pro	missense_variant	13/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.3166A>C	p.Thr1056Pro	missense_variant	13/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127863 AN: 152010 Hom.: 53836 Cov.: 31

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.847

GnomAD3 exomes AF: 0.832 AC: 209232 AN: 251432 Hom.: 87310 AF XY: 0.831 AC XY: 112869 AN XY: 135880

Gnomad AFR exome AF: 0.859

Gnomad AMR exome AF: 0.865

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.807

Gnomad SAS exome AF: 0.828

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.841

Gnomad OTH exome AF: 0.826

GnomAD4 exome AF: 0.844 AC: 1234188 AN: 1461812 Hom.: 521657 Cov.: 61 AF XY: 0.843 AC XY: 613179 AN XY: 727216

Gnomad4 AFR exome AF: 0.857

Gnomad4 AMR exome AF: 0.866

Gnomad4 ASJ exome AF: 0.845

Gnomad4 EAS exome AF: 0.839

Gnomad4 SAS exome AF: 0.823

Gnomad4 FIN exome AF: 0.746

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.837

GnomAD4 genome AF: 0.841 AC: 127963 AN: 152128 Hom.: 53881 Cov.: 31 AF XY: 0.838 AC XY: 62286 AN XY: 74370

Gnomad4 AFR AF: 0.856

Gnomad4 AMR AF: 0.863

Gnomad4 ASJ AF: 0.844

Gnomad4 EAS AF: 0.817

Gnomad4 SAS AF: 0.830

Gnomad4 FIN AF: 0.735

Gnomad4 NFE AF: 0.847

Gnomad4 OTH AF: 0.848

Alfa AF: 0.845 Hom.: 97736

Bravo AF: 0.851

TwinsUK AF: 0.856 AC: 3175

ALSPAC AF: 0.855 AC: 3296

ESP6500AA AF: 0.855 AC: 3768

ESP6500EA AF: 0.851 AC: 7321

ExAC AF: 0.831 AC: 100941

Asia WGS AF: 0.838 AC: 2915 AN: 3478

EpiCase AF: 0.845

EpiControl AF: 0.842

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Neuropathy, hereditary sensory and autonomic, type 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17000706) -

Pseudohypoaldosteronism type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	9.8
Dann	Benign	0.12
DEOGEN2	Benign	0.061	T;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.15	T;T;T;T;T
MetaRNN	Benign	7.2e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.7	N;.;N;.;N
REVEL	Benign	0.053
Sift	Benign	1.0	T;.;T;.;T
Sift4G	Benign	0.34	T;.;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.036
MPC		0.15
ClinPred		0.0012	T
GERP RS		0.64
Varity_R		0.045
gMVP		0.067

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

Other links and lift over

dbSNP: rs956868; hg19: chr12-990912; COSMIC: COSV60040836; COSMIC: COSV60040836;