12-885321-G-C

Variant names:

• chr12-885321-G-C
• rs7955371
• NM_213655.5:c.5273G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018979.4(WNK1):​c.4517G>C​(p.Cys1506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,172 control chromosomes in the GnomAD database, including 803,547 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74464 hom., cov: 31)
  • Exomes 𝑓: 1.0 (729083 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.753

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.164664E-7).
• BP6: Variant 12-885321-G-C is Benign according to our data. Variant chr12-885321-G-C is described in ClinVar as [Benign]. Clinvar id is 261072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-885321-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.5273G>C	p.Cys1758Ser	missense_variant	Exon 19 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.4517G>C	p.Cys1506Ser	missense_variant	Exon 19 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.5273G>C	p.Cys1758Ser	missense_variant	Exon 19 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.4517G>C	p.Cys1506Ser	missense_variant	Exon 19 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.989 AC: 150466 AN: 152176 Hom.: 74414 Cov.: 31

Gnomad AFR AF: 0.961

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.992

GnomAD3 exomes AF: 0.997 AC: 250314 AN: 251096 Hom.: 124782 AF XY: 0.998 AC XY: 135398 AN XY: 135696

Gnomad AFR exome AF: 0.960

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1459989 AN: 1461878 Hom.: 729083 Cov.: 85 AF XY: 0.999 AC XY: 726409 AN XY: 727240

Gnomad4 AFR exome AF: 0.958

Gnomad4 AMR exome AF: 0.997

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.997

GnomAD4 genome AF: 0.989 AC: 150575 AN: 152294 Hom.: 74464 Cov.: 31 AF XY: 0.989 AC XY: 73667 AN XY: 74460

Gnomad4 AFR AF: 0.961

Gnomad4 AMR AF: 0.996

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.992

Alfa AF: 0.957 Hom.: 54593

Bravo AF: 0.987

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.959 AC: 4225

ESP6500EA AF: 1.00 AC: 8600

ExAC AF: 0.996 AC: 120968

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuropathy, hereditary sensory and autonomic, type 2A Benign:2

Jun 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pseudohypoaldosteronism type 2C Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.1
DANN	Benign	0.29
DEOGEN2	Benign	0.065	T;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.027	T;T;T;T;T
MetaRNN	Benign	9.2e-7	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	.;.;N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.9	N;.;N;.;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;.;T;.;T
Sift4G	Benign	0.87	T;.;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.043
MutPred		0.24		.;.;Gain of glycosylation at C1506 (P = 0.0182);.;.;
MPC		0.15
ClinPred		0.0014	T
GERP RS		5.3
Varity_R		0.031
gMVP		0.038

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: rs7955371; hg19: chr12-994487;