NM_213655.5:c.6224C>T

Variant names:

• chr12-890472-C-T
• rs17755373
• NM_213655.5:c.6224C>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_213655.5(WNK1):​c.6224C>T​(p.Pro2075Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0129 in 1,614,040 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 31)
  • Exomes 𝑓: 0.013 (234 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.88
• Publications: 16 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=0.0032887757).
• BP6: Variant 12-890472-C-T is Benign according to our data. Variant chr12-890472-C-T is described in ClinVar as Benign. ClinVar VariationId is 310836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0106 (1617/152228) while in subpopulation SAS AF = 0.055 (265/4822). AF 95% confidence interval is 0.0495. There are 19 homozygotes in GnomAd4. There are 889 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213655.5. 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.6224C>T	p.Pro2075Leu	missense	Exon 22 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.5468C>T	p.Pro1823Leu	missense	Exon 22 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.6248C>T	p.Pro2083Leu	missense	Exon 22 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.6224C>T	p.Pro2075Leu	missense	Exon 22 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.5468C>T	p.Pro1823Leu	missense	Exon 22 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.6707C>T	p.Pro2236Leu	missense	Exon 23 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1620 AN: 152110 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0165 AC: 4146 AN: 251436 AF XY: 0.0189

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0132 AC: 19248 AN: 1461812 Hom.: 234 Cov.: 31 AF XY: 0.0145 AC XY: 10520 AN XY: 727206

African (AFR) AF: 0.00200 AC: 67 AN: 33480

American (AMR) AF: 0.00534 AC: 239 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 878 AN: 26132

East Asian (EAS) AF: 0.0134 AC: 530 AN: 39694

South Asian (SAS) AF: 0.0472 AC: 4068 AN: 86252

European-Finnish (FIN) AF: 0.0139 AC: 744 AN: 53416

Middle Eastern (MID) AF: 0.0348 AC: 201 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11475 AN: 1111954

Other (OTH) AF: 0.0173 AC: 1046 AN: 60392

GnomAD4 genome AF: 0.0106 AC: 1617 AN: 152228 Hom.: 19 Cov.: 31 AF XY: 0.0119 AC XY: 889 AN XY: 74434

African (AFR) AF: 0.00238 AC: 99 AN: 41538

American (AMR) AF: 0.00667 AC: 102 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5178

South Asian (SAS) AF: 0.0550 AC: 265 AN: 4822

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10598

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 741 AN: 68014

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0116 Hom.: 43

Bravo AF: 0.00888

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0129 AC: 111

ExAC AF: 0.0167 AC: 2031

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (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	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.9
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		0.83	P
Vest4		0.40
MPC		0.12
ClinPred		0.051	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.11
gMVP		0.12
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17755373; hg19: chr12-999638;