12-754339-A-C

Variant names:

• chr12-754339-A-C
• rs11064518
• NM_213655.5:c.759+15A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_213655.5(WNK1):​c.759+15A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,154 control chromosomes in the GnomAD database, including 1,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (414 hom., cov: 33)
  • Exomes 𝑓: 0.024 (993 hom.)
• Consequence: WNK1 NM_213655.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.378
• Publications: 4 publications found

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]

WNK1 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• pseudohypoaldosteronism type 2C

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-754339-A-C is Benign according to our data. Variant chr12-754339-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.759+15A>C		intron_variant	Intron 1 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.759+15A>C		intron_variant	Intron 1 of 27	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.759+15A>C		intron_variant	Intron 1 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.759+15A>C		intron_variant	Intron 1 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.0532 AC: 8090 AN: 152112 Hom.: 412 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0420 AC: 10422 AN: 248314 AF XY: 0.0358

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0363

GnomAD4 exome AF: 0.0241 AC: 35263 AN: 1460924 Hom.: 993 Cov.: 88 AF XY: 0.0232 AC XY: 16889 AN XY: 726772

African (AFR) AF: 0.121 AC: 4057 AN: 33478

American (AMR) AF: 0.143 AC: 6398 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 748 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0225 AC: 1941 AN: 86258

European-Finnish (FIN) AF: 0.0146 AC: 764 AN: 52486

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5768

European-Non Finnish (NFE) AF: 0.0174 AC: 19403 AN: 1111990

Other (OTH) AF: 0.0295 AC: 1781 AN: 60386

GnomAD4 genome AF: 0.0533 AC: 8112 AN: 152230 Hom.: 414 Cov.: 33 AF XY: 0.0526 AC XY: 3912 AN XY: 74428

African (AFR) AF: 0.115 AC: 4775 AN: 41522

American (AMR) AF: 0.109 AC: 1667 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4830

European-Finnish (FIN) AF: 0.0140 AC: 148 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1222 AN: 68012

Other (OTH) AF: 0.0432 AC: 91 AN: 2108

Alfa AF: 0.0482 Hom.: 116

Bravo AF: 0.0635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 02, 2018

Athena Diagnostics

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

- -

not specified Benign:1

Mar 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	13
DANN	Benign	0.55
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11064518; hg19: chr12-863505;