12-865160-G-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.2190G>C(p.Leu730Phe) variant causes a missense change. The variant allele was found at a frequency of 0.107 in 1,531,320 control chromosomes in the GnomAD database, including 9,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1086 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8174 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.70

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=8.736253E-4).
• BP6: Variant 12-865160-G-C is Benign according to our data. Variant chr12-865160-G-C is described in ClinVar as [Benign]. Clinvar id is 674047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-865160-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.2190G>C	p.Leu730Phe	missense_variant	9/28	ENST00000340908.9
WNK1	NM_018979.4	c.2139+2890G>C		intron_variant		ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.2190G>C	p.Leu730Phe	missense_variant	9/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.2139+2890G>C		intron_variant		1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.114 AC: 16983 AN: 149112 Hom.: 1082 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0828

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0992

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.115 AC: 15132 AN: 131620 Hom.: 1002 AF XY: 0.110 AC XY: 7873 AN XY: 71572

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.217

Gnomad SAS exome AF: 0.0768

Gnomad FIN exome AF: 0.0838

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.106 AC: 146164 AN: 1382090 Hom.: 8174 Cov.: 40 AF XY: 0.104 AC XY: 71202 AN XY: 681716

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.0788

Gnomad4 FIN exome AF: 0.0841

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.114 AC: 17010 AN: 149230 Hom.: 1086 Cov.: 32 AF XY: 0.114 AC XY: 8259 AN XY: 72740

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0992

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.0874

Gnomad4 FIN AF: 0.0766

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0966 Hom.: 555

Bravo AF: 0.117

TwinsUK AF: 0.0936 AC: 347

ALSPAC AF: 0.101 AC: 388

ExAC AF: 0.0736 AC: 1333

Asia WGS AF: 0.134 AC: 466 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.00087	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Uncertain	-3.5	D
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.70	T
Vest4		0.050
ClinPred		0.083	T
GERP RS		3.8
gMVP		0.0075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11611231; hg19: chr12-974326; COSMIC: COSV60027497; COSMIC: COSV60027497;