rs1555164556

Variant names:

• chr12-908776-A-G
• rs1555164556
• NM_213655.5:c.7889A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018979.4(WNK1):​c.7133A>G​(p.Asn2378Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,240,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2378K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.40
• 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018979.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	NM_213655.5	MANE Plus Clinical	c.7889A>G	p.Asn2630Ser	missense	Exon 28 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.7133A>G	p.Asn2378Ser	missense	Exon 28 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.7913A>G	p.Asn2638Ser	missense	Exon 28 of 28	NP_001171914.1	Q9H4A3-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.7889A>G	p.Asn2630Ser	missense	Exon 28 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.7133A>G	p.Asn2378Ser	missense	Exon 28 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.8486A>G	p.Asn2829Ser	missense	Exon 31 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000113 AC: 14 AN: 1240660 Hom.: 0 Cov.: 34 AF XY: 0.0000130 AC XY: 8 AN XY: 615356

African (AFR) AF: 0.00 AC: 0 AN: 26958

American (AMR) AF: 0.00 AC: 0 AN: 37976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17784

East Asian (EAS) AF: 0.00 AC: 0 AN: 18970

South Asian (SAS) AF: 0.00 AC: 0 AN: 84288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4600

European-Non Finnish (NFE) AF: 0.0000144 AC: 14 AN: 969754

Other (OTH) AF: 0.00 AC: 0 AN: 45700

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	2.0	M
PhyloP100		8.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.15		Gain of phosphorylation at N2378 (P = 0.0382)
MVP		0.77
MPC		0.51
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.40
Mutation Taster		=72/28	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: rs1555164556; hg19: chr12-1017942;