rs1555158125

chr12-896546-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_213655.5(WNK1):c.6815G>A(p.Ser2272Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S2272S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, WNK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.1141876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.6815G>A	p.Ser2272Asn	missense_variant	24/28	ENST00000340908.9
WNK1	NM_018979.4	c.6059G>A	p.Ser2020Asn	missense_variant	24/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.6815G>A	p.Ser2272Asn	missense_variant	24/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.6059G>A	p.Ser2020Asn	missense_variant	24/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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

Invitae

Sep 03, 2023

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2272 of the WNK1 protein (p.Ser2272Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WNK1 protein function. ClinVar contains an entry for this variant (Variation ID: 471203). This variant has not been reported in the literature in individuals affected with WNK1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Benign	0.81
DEOGEN2	Benign	0.090	T;.;T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.65	T;T;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N;N;N;.;N
REVEL	Benign	0.099
Sift	Benign	0.063	T;D;T;.;T
Sift4G	Benign	0.59	T;.;T;T;T
Polyphen		0.49	P;.;B;.;.
Vest4		0.16
MutPred		0.21		.;.;Loss of phosphorylation at S2020 (P = 0.0064);.;.;
MVP		0.19
MPC		0.12
ClinPred		0.26	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.050
gMVP		0.14

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: rs1555158125; hg19: chr12-1005712;