rs2301880

chr12-894671-C-T

Variant summary

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

The NM_213655.5(WNK1):c.6339+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,586,762 control chromosomes in the GnomAD database, including 47,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4743 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42519 hom.)
• Consequence: WNK1 NM_213655.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.836

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 (BayesDel_noAF=-0.94).
• BP6: Variant 12-894671-C-T is Benign according to our data. Variant chr12-894671-C-T is described in ClinVar as [Benign]. Clinvar id is 674135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-894671-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.5583+36C>T		intron_variant		ENST00000315939.11
WNK1	NM_213655.5	c.6339+36C>T		intron_variant		ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.5583+36C>T		intron_variant		1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.6339+36C>T		intron_variant		5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37669 AN: 151916 Hom.: 4738 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.265

GnomAD3 exomes AF: 0.236 AC: 59206 AN: 251250 Hom.: 7279 AF XY: 0.236 AC XY: 32103 AN XY: 135800

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.244

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.242 AC: 347147 AN: 1434730 Hom.: 42519 Cov.: 26 AF XY: 0.242 AC XY: 173385 AN XY: 715544

Gnomad4 AFR exome AF: 0.283

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.248 AC: 37703 AN: 152032 Hom.: 4743 Cov.: 32 AF XY: 0.245 AC XY: 18223 AN XY: 74292

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.270

Alfa AF: 0.252 Hom.: 1118

Bravo AF: 0.252

Asia WGS AF: 0.255 AC: 885 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	8.1
Dann	Benign	0.63

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: rs2301880; hg19: chr12-1003837; COSMIC: COSV104411037; COSMIC: COSV104411037;