12-753823-T-G

Position:

• chr12-753823-T-G

Variant summary

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

The NM_018979.4(WNK1):​c.258T>G​(p.Cys86Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C86C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.839

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 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.258T>G	p.Cys86Trp	missense_variant	1/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.258T>G	p.Cys86Trp	missense_variant	1/28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.258T>G	p.Cys86Trp	missense_variant	1/28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.258T>G	p.Cys86Trp	missense_variant	1/28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 110

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;D;.;.;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.1	.;M;M;M;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.4	D;D;D;.;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D;.;D;D
Sift4G	Uncertain	0.0050	D;.;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D
Vest4		0.65
MutPred		0.45		Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);Gain of MoRF binding (P = 0.0124);
MVP		0.50
MPC		0.99
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.37

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: rs3168640; hg19: chr12-862989;