rs146861951

chr12-885368-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_213655.5(WNK1):c.5320G>A(p.Val1774Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,613,798 control chromosomes in the GnomAD database, including 4 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (4 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.29

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 -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, WNK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.003797263).
• BP6: Variant 12-885368-G-A is Benign according to our data. Variant chr12-885368-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 310830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.5320G>A	p.Val1774Met	missense_variant	19/28	ENST00000340908.9
WNK1	NM_018979.4	c.4564G>A	p.Val1522Met	missense_variant	19/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.5320G>A	p.Val1774Met	missense_variant	19/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.4564G>A	p.Val1522Met	missense_variant	19/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000510 AC: 128 AN: 250868 Hom.: 0 AF XY: 0.000568 AC XY: 77 AN XY: 135614

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000556 AC: 813 AN: 1461516 Hom.: 4 Cov.: 36 AF XY: 0.000567 AC XY: 412 AN XY: 727100

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.000823

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000581

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74456

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.073	T;.;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0038	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;.;N;.;N
REVEL	Benign	0.022
Sift	Benign	0.14	T;.;T;.;T
Sift4G	Benign	0.18	T;.;T;T;T
Polyphen		0.24	B;.;B;.;.
Vest4		0.083
MVP		0.12
MPC		0.19
ClinPred		0.012	T
GERP RS		4.4
Varity_R		0.041
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: rs146861951; hg19: chr12-994534; COSMIC: COSV100268740; COSMIC: COSV100268740;