12-896639-G-T

Position:

• chr12-896639-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_018979.4(WNK1):​c.6152G>T​(p.Ser2051Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WNK1. . Gene score misZ 2.1626 (greater than the threshold 3.09). Trascript score misZ 4.652 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory and autonomic, type 2A, hereditary sensory and autonomic neuropathy type 2, pseudohypoaldosteronism type 2C.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5	c.6908G>T	p.Ser2303Ile	missense_variant	24/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.6152G>T	p.Ser2051Ile	missense_variant	24/28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.6908G>T	p.Ser2303Ile	missense_variant	24/28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.6152G>T	p.Ser2051Ile	missense_variant	24/28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248296 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457928 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 10, 2017

This sequence change replaces serine with isoleucine at codon 2051 of the WNK1 protein (p.Ser2051Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs561238194, ExAC 0.002%) but has not been reported in the literature in individuals with a WNK1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Uncertain	2.0	.;.;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;.;D;.;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Uncertain	0.011	D;.;D;D;D
Polyphen		0.99	D;.;D;.;.
Vest4		0.77
MutPred		0.18		.;.;Loss of phosphorylation at S2051 (P = 0.0107);.;.;
MVP		0.58
MPC		0.61
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.79
gMVP		0.29

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: rs561238194; hg19: chr12-1005805;