rs72647375

Variant names:

• chr12-754339-A-ACTT
• rs398088143
• NM_213655.5:c.759+16_759+18dupCTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_213655.5(WNK1):​c.759+16_759+18dupCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,613,104 control chromosomes in the GnomAD database, including 3,750 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (660 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3090 hom.)
• Consequence: WNK1 NM_213655.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0360
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 12-754339-A-ACTT is Benign according to our data. Variant chr12-754339-A-ACTT is described in ClinVar as Benign. ClinVar VariationId is 310547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.759+16_759+18dupCTT		intron_variant	Intron 1 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.759+16_759+18dupCTT		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+15_759+16insCTT		intron_variant	Intron 1 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.759+15_759+16insCTT		intron_variant	Intron 1 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.0835 AC: 12692 AN: 152090 Hom.: 659 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0882

GnomAD2 exomes AF: 0.0576 AC: 14315 AN: 248314 AF XY: 0.0554

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.0953

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0706

Gnomad NFE exome AF: 0.0670

Gnomad OTH exome AF: 0.0563

GnomAD4 exome AF: 0.0607 AC: 88675 AN: 1460896 Hom.: 3090 Cov.: 88 AF XY: 0.0594 AC XY: 43168 AN XY: 726760

African (AFR) AF: 0.143 AC: 4801 AN: 33480

American (AMR) AF: 0.0460 AC: 2057 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0929 AC: 2427 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0104 AC: 897 AN: 86258

European-Finnish (FIN) AF: 0.0653 AC: 3428 AN: 52484

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.0640 AC: 71168 AN: 1111964

Other (OTH) AF: 0.0607 AC: 3667 AN: 60386

GnomAD4 genome AF: 0.0835 AC: 12712 AN: 152208 Hom.: 660 Cov.: 32 AF XY: 0.0821 AC XY: 6111 AN XY: 74420

African (AFR) AF: 0.142 AC: 5886 AN: 41516

American (AMR) AF: 0.0687 AC: 1050 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00952 AC: 46 AN: 4830

European-Finnish (FIN) AF: 0.0696 AC: 738 AN: 10604

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0640 AC: 4355 AN: 68002

Other (OTH) AF: 0.0878 AC: 185 AN: 2108

Alfa AF: 0.0761 Hom.: 95

Bravo AF: 0.0874

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Oct 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 16, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoaldosteronism type 2A Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.036
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398088143; hg19: chr12-863505;