rs752345591

Variant names:

• chr12-753950-G-A
• rs752345591
• NM_213655.5:c.385G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-753950-G-A
• chr12-753950-G-C
• chr12-753950-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_213655.5(WNK1):​c.385G>A​(p.Ala129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,451,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A129S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07592958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.385G>A	p.Ala129Thr	missense_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.385G>A	p.Ala129Thr	missense_variant	Exon 1 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.385G>A	p.Ala129Thr	missense_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.385G>A	p.Ala129Thr	missense_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000911 AC: 2 AN: 219590 AF XY: 0.0000165

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1451018 Hom.: 0 Cov.: 95 AF XY: 0.00000693 AC XY: 5 AN XY: 721284

African (AFR) AF: 0.0000301 AC: 1 AN: 33252

American (AMR) AF: 0.00 AC: 0 AN: 43220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.0000586 AC: 5 AN: 85392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107788

Other (OTH) AF: 0.00 AC: 0 AN: 59910

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000249 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.73
DEOGEN2	Benign	0.061	T;.;T;.;.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.076	T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	.;L;L;L;L;.
PhyloP100		-0.38
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.46	N;N;N;.;N;N
REVEL	Benign	0.082
Sift	Benign	0.38	T;T;T;.;T;T
Sift4G	Benign	0.59	T;.;T;T;T;T
Polyphen		0.0030	B;.;B;.;.;B
Vest4		0.032
MutPred		0.28		Gain of glycosylation at A129 (P = 0.0028);Gain of glycosylation at A129 (P = 0.0028);Gain of glycosylation at A129 (P = 0.0028);Gain of glycosylation at A129 (P = 0.0028);Gain of glycosylation at A129 (P = 0.0028);Gain of glycosylation at A129 (P = 0.0028);
MVP		0.25
MPC		0.71
ClinPred		0.019	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.061
Mutation Taster		=92/8	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: rs752345591; hg19: chr12-863116;