rs12828016

Variant names:

• chr12-889199-G-T
• rs12828016
• NM_213655.5:c.6180G>T

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.6180G>T​(p.Met2060Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,612,936 control chromosomes in the GnomAD database, including 123,394 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2060V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.41 (13066 hom., cov: 32)
  • Exomes 𝑓: 0.39 (110328 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.446
• Publications: 64 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 (MetaRNN=2.491094E-5).
• BP6: Variant 12-889199-G-T is Benign according to our data. Variant chr12-889199-G-T is described in ClinVar as Benign. ClinVar VariationId is 261073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

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.6180G>T	p.Met2060Ile	missense	Exon 21 of 28	NP_998820.3
	WNK1	NM_018979.4	MANE Select	c.5424G>T	p.Met1808Ile	missense	Exon 21 of 28	NP_061852.3
	WNK1	NM_001184985.2		c.6204G>T	p.Met2068Ile	missense	Exon 21 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.6180G>T	p.Met2060Ile	missense	Exon 21 of 28	ENSP00000341292.5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.5424G>T	p.Met1808Ile	missense	Exon 21 of 28	ENSP00000313059.6
	WNK1	ENST00000530271.6	TSL:1	c.6663G>T	p.Met2221Ile	missense	Exon 22 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61765 AN: 151874 Hom.: 13054 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.370 AC: 92947 AN: 251292 AF XY: 0.375

Gnomad AFR exome AF: 0.513

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.386 AC: 563448 AN: 1460944 Hom.: 110328 Cov.: 39 AF XY: 0.388 AC XY: 281819 AN XY: 726856

African (AFR) AF: 0.511 AC: 17090 AN: 33452

American (AMR) AF: 0.294 AC: 13167 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 10691 AN: 26116

East Asian (EAS) AF: 0.323 AC: 12820 AN: 39672

South Asian (SAS) AF: 0.446 AC: 38452 AN: 86236

European-Finnish (FIN) AF: 0.290 AC: 15472 AN: 53384

Middle Eastern (MID) AF: 0.490 AC: 2824 AN: 5768

European-Non Finnish (NFE) AF: 0.386 AC: 429418 AN: 1111228

Other (OTH) AF: 0.390 AC: 23514 AN: 60366

GnomAD4 genome AF: 0.407 AC: 61814 AN: 151992 Hom.: 13066 Cov.: 32 AF XY: 0.401 AC XY: 29825 AN XY: 74302

African (AFR) AF: 0.505 AC: 20910 AN: 41412

American (AMR) AF: 0.341 AC: 5215 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1436 AN: 3466

East Asian (EAS) AF: 0.286 AC: 1478 AN: 5168

South Asian (SAS) AF: 0.461 AC: 2225 AN: 4826

European-Finnish (FIN) AF: 0.283 AC: 2989 AN: 10566

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26269 AN: 67966

Other (OTH) AF: 0.432 AC: 909 AN: 2106

Alfa AF: 0.395 Hom.: 61363

Bravo AF: 0.412

TwinsUK AF: 0.394 AC: 1462

ALSPAC AF: 0.384 AC: 1480

ESP6500AA AF: 0.510 AC: 2248

ESP6500EA AF: 0.391 AC: 3363

ExAC AF: 0.377 AC: 45722

Asia WGS AF: 0.412 AC: 1433 AN: 3478

EpiCase AF: 0.408

EpiControl AF: 0.404

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Neuropathy, hereditary sensory and autonomic, type 2A (2)
-	-	2	not provided (2)
-	-	1	Pseudohypoaldosteronism type 2C (1)
-	-	1	Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.077	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.45
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.011
Sift	Benign	0.21	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.28		Loss of catalytic residue at M1808 (P = 0.0215)
MPC		0.13
ClinPred		0.0011	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs12828016; hg19: chr12-998365; COSMIC: COSV60032006; COSMIC: COSV60032006;