12-861247-A-G

Variant names:

• chr12-861247-A-G
• rs149388376
• NM_213655.5:c.1855A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_213655.5(WNK1):​c.1855A>G​(p.Thr619Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,144 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T619P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.730
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011191517).
• BP6: Variant 12-861247-A-G is Benign according to our data. Variant chr12-861247-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310741.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00086 (131/152272) while in subpopulation NFE AF = 0.00149 (101/68012). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213655.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	NM_213655.5	MANE Plus Clinical	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	NP_998820.3
	WNK1	NM_018979.4	MANE Select	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	NP_061852.3
	WNK1	NM_001184985.2		c.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	NP_001171914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	ENSP00000341292.5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	ENSP00000313059.6
	WNK1	ENST00000530271.6	TSL:1	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000793 AC: 199 AN: 250818 AF XY: 0.000804

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00140 AC: 2048 AN: 1461872 Hom.: 2 Cov.: 33 AF XY: 0.00134 AC XY: 973 AN XY: 727236

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00172 AC: 1915 AN: 1111998

Other (OTH) AF: 0.00118 AC: 71 AN: 60392

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.000725 AC XY: 54 AN XY: 74470

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.00124 AC: 19 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 68012

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00109

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000758 AC: 92

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WNK1: PM2:Supporting, BP4

Sep 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The WNK1 c.1855A>G; p.Thr619Ala variant (rs149388376), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 310741). This variant is found in the non-Finnish European population with an overall allele frequency of 0.13% (168/128,558 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.078). However, due to limited information, the clinical significance of the p.Thr619Ala variant is uncertain at this time.

Inborn genetic diseases Uncertain:1

Mar 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T619A variant (also known as c.1855A>G), located in coding exon 7 of the WNK1 gene, results from an A to G substitution at nucleotide position 1855. The threonine at codon 619 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not specified Benign:1

May 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: WNK1 c.1855A>G (p.Thr619Ala) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00079 in 250818 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2-fold of the estimated maximal expected allele frequency for a pathogenic variant in WNK1 causing Neuropathy, hereditary sensory and autonomic, type 2A phenotype (0.0011), suggesting the variant may be benign. To our knowledge, no occurrence of c.1855A>G in individuals affected with Neuropathy, hereditary sensory and autonomic, type 2A and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 310741). Based on the evidence outlined above, the variant was classified as likely benign.

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

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WNK1-related disorder Benign:1

Feb 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.73
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.078
Sift	Benign	0.23	T
Sift4G	Benign	0.81	T
Polyphen		0.0090	B
Vest4		0.12
MVP		0.11
MPC		0.12
ClinPred		0.015	T
GERP RS		3.4
PromoterAI		0.012	Neutral
Varity_R		0.061
gMVP		0.17
Mutation Taster		=83/17	polymorphism

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: rs149388376; hg19: chr12-970413;