rs143890340

Positions:

• chr12-878278-A-C
• chr12-878278-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The ENST00000315939.11(WNK1):​c.2290A>C​(p.Thr764Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T764A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WNK1 ENST00000315939.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.493

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 Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03209898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5	c.3784A>C	p.Thr1262Pro	missense_variant	12/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.2290A>C	p.Thr764Pro	missense_variant	10/28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.3784A>C	p.Thr1262Pro	missense_variant	12/28	5	NM_213655.5	ENSP00000341292	A2
WNK1	ENST00000315939.11	c.2290A>C	p.Thr764Pro	missense_variant	10/28	1	NM_018979.4	ENSP00000313059	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.72
DEOGEN2	Benign	0.057	T;.;T;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.58	T;T;T;T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.032	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	.;.;N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;.;N;.;N;D;.
REVEL	Benign	0.082
Sift	Benign	0.58	T;.;D;.;D;T;.
Sift4G	Benign	0.29	T;.;T;T;T;T;D
Polyphen		0.0	B;.;B;.;.;.;.
Vest4		0.12
MutPred		0.11		.;.;Gain of glycosylation at T764 (P = 0.0333);.;.;.;.;
MVP		0.11
MPC		0.15
ClinPred		0.027	T
GERP RS		-10
Varity_R		0.085
gMVP		0.043

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: rs143890340; hg19: chr12-987444;