rs34728563

chr12-859370-T-C

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.1526T>C(p.Ile509Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,612,272 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (45 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.83

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=0.0046376586).
• BP6: Variant 12-859370-T-C is Benign according to our data. Variant chr12-859370-T-C is described in ClinVar as [Benign]. Clinvar id is 310738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-859370-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.1526T>C	p.Ile509Thr	missense_variant	6/28	ENST00000340908.9
WNK1	NM_018979.4	c.1526T>C	p.Ile509Thr	missense_variant	6/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.1526T>C	p.Ile509Thr	missense_variant	6/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.1526T>C	p.Ile509Thr	missense_variant	6/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2282 AN: 152064 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00403 AC: 1009 AN: 250150 Hom.: 23 AF XY: 0.00304 AC XY: 411 AN XY: 135344

Gnomad AFR exome AF: 0.0508

Gnomad AMR exome AF: 0.00380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00169 AC: 2474 AN: 1460090 Hom.: 45 Cov.: 31 AF XY: 0.00147 AC XY: 1071 AN XY: 726428

Gnomad4 AFR exome AF: 0.0523

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.0150 AC: 2282 AN: 152182 Hom.: 55 Cov.: 32 AF XY: 0.0147 AC XY: 1093 AN XY: 74410

Gnomad4 AFR AF: 0.0516

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00298 Hom.: 13

Bravo AF: 0.0174

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00466 AC: 566

Asia WGS AF: 0.00260 AC: 9 AN: 3474

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 24, 2020

- -

Pseudohypoaldosteronism type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Benign	0.93
DEOGEN2	Benign	0.093	T;.;T;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T;T;T;T
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N;N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N;N;N;.;N
REVEL	Benign	0.094
Sift	Benign	0.62	T;T;T;.;T
Sift4G	Benign	0.30	T;.;T;T;T
Polyphen		0.037	B;.;B;.;.
Vest4		0.41
MVP		0.068
MPC		1.9
ClinPred		0.027	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.91

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: rs34728563; hg19: chr12-968536; COSMIC: COSV104411133; COSMIC: COSV104411133;