rs11554421

Variant names:

• chr12-753986-G-A
• rs11554421
• NM_213655.5:c.421G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018979.4(WNK1):​c.421G>A​(p.Ala141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,591,360 control chromosomes in the GnomAD database, including 12,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A141V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.099 (970 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11842 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.186
• Publications: 26 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025852323).
• BP6: Variant 12-753986-G-A is Benign according to our data. Variant chr12-753986-G-A is described in ClinVar as Benign. ClinVar VariationId is 137927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018979.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	NM_213655.5	MANE Plus Clinical	c.421G>A	p.Ala141Thr	missense	Exon 1 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.421G>A	p.Ala141Thr	missense	Exon 1 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.421G>A	p.Ala141Thr	missense	Exon 1 of 28	NP_001171914.1	Q9H4A3-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.421G>A	p.Ala141Thr	missense	Exon 1 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.421G>A	p.Ala141Thr	missense	Exon 1 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.421G>A	p.Ala141Thr	missense	Exon 1 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.0987 AC: 15015 AN: 152132 Hom.: 970 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0725

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0584

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0893

GnomAD2 exomes AF: 0.123 AC: 24434 AN: 199102 AF XY: 0.130

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.0544

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.0672

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.122 AC: 176098 AN: 1439110 Hom.: 11842 Cov.: 94 AF XY: 0.124 AC XY: 88734 AN XY: 714316

African (AFR) AF: 0.0264 AC: 871 AN: 32938

American (AMR) AF: 0.0549 AC: 2238 AN: 40748

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2926 AN: 25672

East Asian (EAS) AF: 0.0475 AC: 1829 AN: 38516

South Asian (SAS) AF: 0.159 AC: 13417 AN: 84276

European-Finnish (FIN) AF: 0.230 AC: 11574 AN: 50290

Middle Eastern (MID) AF: 0.170 AC: 963 AN: 5670

European-Non Finnish (NFE) AF: 0.123 AC: 135048 AN: 1101514

Other (OTH) AF: 0.122 AC: 7232 AN: 59486

GnomAD4 genome AF: 0.0986 AC: 15015 AN: 152250 Hom.: 970 Cov.: 33 AF XY: 0.104 AC XY: 7727 AN XY: 74446

African (AFR) AF: 0.0304 AC: 1264 AN: 41548

American (AMR) AF: 0.0724 AC: 1109 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3468

East Asian (EAS) AF: 0.0586 AC: 303 AN: 5174

South Asian (SAS) AF: 0.147 AC: 710 AN: 4820

European-Finnish (FIN) AF: 0.241 AC: 2560 AN: 10602

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8348 AN: 68008

Other (OTH) AF: 0.0879 AC: 186 AN: 2116

Alfa AF: 0.109 Hom.: 655

Bravo AF: 0.0809

TwinsUK AF: 0.124 AC: 460

ALSPAC AF: 0.123 AC: 474

ESP6500AA AF: 0.0255 AC: 107

ESP6500EA AF: 0.108 AC: 896

ExAC AF: 0.107 AC: 12721

Asia WGS AF: 0.0920 AC: 321 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Pseudohypoaldosteronism type 2C (1)
-	-	1	Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.19
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.086
Sift	Uncertain	0.024	D
Sift4G	Benign	0.55	T
Polyphen		0.11	B
Vest4		0.20
MPC		0.71
ClinPred		0.012	T
GERP RS		4.3
Varity_R		0.073
gMVP		0.18
Mutation Taster		=95/5	polymorphism (auto)

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: rs11554421; hg19: chr12-863152; COSMIC: COSV60031163;