12-865160-G-C

Variant names:

• chr12-865160-G-C
• rs11611231
• NM_213655.5:c.2190G>C

Variant summary

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

The NM_213655.5(WNK1):​c.2190G>C​(p.Leu730Phe) variant causes a missense change. The variant allele was found at a frequency of 0.107 in 1,531,320 control chromosomes in the GnomAD database, including 9,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1086 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8174 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.70
• Publications: 20 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), G2P, Ambry Genetics, ClinGen
• 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

ENSG00000285704 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.736253E-4).
• BP6: Variant 12-865160-G-C is Benign according to our data. Variant chr12-865160-G-C is described in ClinVar as Benign. ClinVar VariationId is 674047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

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.2190G>C	p.Leu730Phe	missense	Exon 9 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.2139+2890G>C		intron	N/A	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.2140-2706G>C		intron	N/A	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.2190G>C	p.Leu730Phe	missense	Exon 9 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.2139+2890G>C		intron	N/A	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.2140-2706G>C		intron	N/A	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.114 AC: 16983 AN: 149112 Hom.: 1082 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0828

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0992

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.115 AC: 15132 AN: 131620 AF XY: 0.110

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.0838

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.106 AC: 146164 AN: 1382090 Hom.: 8174 Cov.: 40 AF XY: 0.104 AC XY: 71202 AN XY: 681716

African (AFR) AF: 0.132 AC: 4174 AN: 31562

American (AMR) AF: 0.139 AC: 4924 AN: 35512

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2614 AN: 25116

East Asian (EAS) AF: 0.222 AC: 7928 AN: 35698

South Asian (SAS) AF: 0.0788 AC: 6231 AN: 79094

European-Finnish (FIN) AF: 0.0841 AC: 2849 AN: 33888

Middle Eastern (MID) AF: 0.0829 AC: 472 AN: 5694

European-Non Finnish (NFE) AF: 0.103 AC: 110837 AN: 1077692

Other (OTH) AF: 0.106 AC: 6135 AN: 57834

GnomAD4 genome AF: 0.114 AC: 17010 AN: 149230 Hom.: 1086 Cov.: 32 AF XY: 0.114 AC XY: 8259 AN XY: 72740

African (AFR) AF: 0.131 AC: 5327 AN: 40648

American (AMR) AF: 0.108 AC: 1605 AN: 14876

Ashkenazi Jewish (ASJ) AF: 0.0992 AC: 340 AN: 3426

East Asian (EAS) AF: 0.220 AC: 1123 AN: 5110

South Asian (SAS) AF: 0.0874 AC: 403 AN: 4610

European-Finnish (FIN) AF: 0.0766 AC: 779 AN: 10176

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.106 AC: 7104 AN: 67164

Other (OTH) AF: 0.116 AC: 236 AN: 2034

Alfa AF: 0.0966 Hom.: 555

Bravo AF: 0.117

TwinsUK AF: 0.0936 AC: 347

ALSPAC AF: 0.101 AC: 388

ExAC AF: 0.0736 AC: 1333

Asia WGS AF: 0.134 AC: 466 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.00087	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.7
PROVEAN	Uncertain	-3.5	D
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.70	T
Vest4		0.050
ClinPred		0.083	T
GERP RS		3.8
gMVP		0.0075
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11611231; hg19: chr12-974326; COSMIC: COSV60027497; COSMIC: COSV60027497;