rs138446333

Variant names:

• chr12-880783-C-A
• rs138446333
• NM_018979.4:c.2895C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-880783-C-A
• chr12-880783-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018979.4(WNK1):​c.2895C>A​(p.Asn965Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N965N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18238136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_018979.4	c.2895C>A	p.Asn965Lys	missense_variant	Exon 12 of 28	ENST00000315939.11	NP_061852.3
WNK1	NM_213655.5	c.3868-909C>A		intron_variant	Intron 12 of 27	ENST00000340908.9	NP_998820.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000315939.11	c.2895C>A	p.Asn965Lys	missense_variant	Exon 12 of 28	1	NM_018979.4	ENSP00000313059.6
WNK1	ENST00000340908.9	c.3868-909C>A		intron_variant	Intron 12 of 27	5	NM_213655.5	ENSP00000341292.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.19	.;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	.;N;.;.
PhyloP100		3.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	.;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.042	.;D;D;D
Sift4G	Benign	0.90	.;T;T;T
Polyphen		0.020	.;B;.;.
Vest4		0.20
MutPred		0.45		.;Gain of methylation at N965 (P = 0.0114);.;.;
MVP		0.10
MPC		0.26
ClinPred		0.42	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
Mutation Taster		=88/12	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: rs138446333; hg19: chr12-989949;