rs147099510

Positions:

• chr12-871331-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_213655.5(WNK1):​c.3700A>G​(p.Ile1234Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,614,186 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (16 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.257

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, WNK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032319725).
• BP6: Variant 12-871331-A-G is Benign according to our data. Variant chr12-871331-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 310745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-871331-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.3700A>G	p.Ile1234Val	missense_variant	11/28	ENST00000340908.9
WNK1	NM_018979.4	c.2206A>G	p.Ile736Val	missense_variant	9/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.3700A>G	p.Ile1234Val	missense_variant	11/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.2206A>G	p.Ile736Val	missense_variant	9/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00185 AC: 464 AN: 251464 Hom.: 6 AF XY: 0.00227 AC XY: 308 AN XY: 135904

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00689

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00146 AC: 2130 AN: 1461868 Hom.: 16 Cov.: 31 AF XY: 0.00164 AC XY: 1192 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00698

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74490

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.000967

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00211 AC: 256

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	WNK1: BP4, BS2 -

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.1
DANN	Benign	0.81
DEOGEN2	Benign	0.057	T;.;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.0032	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.12	N;.;N;.;N;.
REVEL	Benign	0.023
Sift	Benign	1.0	T;.;T;.;T;.
Sift4G	Benign	1.0	T;.;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.
Vest4		0.044
MVP		0.068
MPC		0.097
ClinPred		0.0029	T
GERP RS		-2.0
Varity_R		0.014
gMVP		0.033

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: rs147099510; hg19: chr12-980497;