rs34880640

Variant names:

• chr12-754011-C-T
• rs34880640
• NM_213655.5:c.446C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018979.4(WNK1):​c.446C>T​(p.Ala149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,586,632 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A149A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (29 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.808
• Publications: 8 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=0.0026817322).
• BP6: Variant 12-754011-C-T is Benign according to our data. Variant chr12-754011-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00143 (218/152310) while in subpopulation EAS AF = 0.0329 (170/5160). AF 95% confidence interval is 0.0289. There are 1 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 29 AR,AD gene

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.446C>T	p.Ala149Val	missense	Exon 1 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.446C>T	p.Ala149Val	missense	Exon 1 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.446C>T	p.Ala149Val	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.446C>T	p.Ala149Val	missense	Exon 1 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.446C>T	p.Ala149Val	missense	Exon 1 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.446C>T	p.Ala149Val	missense	Exon 1 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00332 AC: 638 AN: 191920 AF XY: 0.00337

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0321

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.000398

GnomAD4 exome AF: 0.00142 AC: 2031 AN: 1434322 Hom.: 29 Cov.: 94 AF XY: 0.00156 AC XY: 1113 AN XY: 711426

African (AFR) AF: 0.0000913 AC: 3 AN: 32852

American (AMR) AF: 0.0000253 AC: 1 AN: 39556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25634

East Asian (EAS) AF: 0.0343 AC: 1311 AN: 38248

South Asian (SAS) AF: 0.00595 AC: 499 AN: 83932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50260

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5588

European-Non Finnish (NFE) AF: 0.0000582 AC: 64 AN: 1098926

Other (OTH) AF: 0.00255 AC: 151 AN: 59326

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74482

African (AFR) AF: 0.000144 AC: 6 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0329 AC: 170 AN: 5160

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00139

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00280 AC: 334

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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	0.089
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.81
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.037
Sift	Benign	0.57	T
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.028
MVP		0.18
MPC		0.73
ClinPred		0.0085	T
GERP RS		-1.4
Varity_R		0.021
gMVP		0.13
Mutation Taster		=99/1	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: rs34880640; hg19: chr12-863177; COSMIC: COSV107331260;