rs17755373

chr12-890472-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213655.5(WNK1):c.6224C>T(p.Pro2075Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0129 in 1,614,040 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 31)
  • Exomes 𝑓: 0.013 (234 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.88

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=0.0032887757).
• BP6: Variant 12-890472-C-T is Benign according to our data. Variant chr12-890472-C-T is described in ClinVar as [Benign]. Clinvar id is 310836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-890472-C-T is described in Lovd as [Likely_benign]. Variant chr12-890472-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0106 (1617/152228) while in subpopulation SAS AF= 0.055 (265/4822). AF 95% confidence interval is 0.0495. There are 19 homozygotes in gnomad4. There are 889 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.6224C>T	p.Pro2075Leu	missense_variant	22/28	ENST00000340908.9
WNK1	NM_018979.4	c.5468C>T	p.Pro1823Leu	missense_variant	22/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.6224C>T	p.Pro2075Leu	missense_variant	22/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.5468C>T	p.Pro1823Leu	missense_variant	22/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1620 AN: 152110 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0165 AC: 4146 AN: 251436 Hom.: 73 AF XY: 0.0189 AC XY: 2567 AN XY: 135906

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.0221

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0132 AC: 19248 AN: 1461812 Hom.: 234 Cov.: 31 AF XY: 0.0145 AC XY: 10520 AN XY: 727206

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00534

Gnomad4 ASJ exome AF: 0.0336

Gnomad4 EAS exome AF: 0.0134

Gnomad4 SAS exome AF: 0.0472

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0106 AC: 1617 AN: 152228 Hom.: 19 Cov.: 31 AF XY: 0.0119 AC XY: 889 AN XY: 74434

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.0325

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0550

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0124 Hom.: 28

Bravo AF: 0.00888

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0129 AC: 111

ExAC AF: 0.0167 AC: 2031

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 29, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	WNK1: BP4, BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Pseudohypoaldosteronism type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Benign	0.89
DEOGEN2	Benign	0.13	T;.;D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.95	D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.3	D;.;D;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.030	D;.;D;D;D
Polyphen		0.83	P;.;P;.;.
Vest4		0.40
MPC		0.12
ClinPred		0.051	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.11
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17755373; hg19: chr12-999638; COSMIC: COSV104411132;