12-862125-C-T

Variant names:

• chr12-862125-C-T
• rs2286007
• NM_213655.5:c.1994C>T

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.1994C>T​(p.Thr665Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0659 in 1,613,962 control chromosomes in the GnomAD database, including 3,853 homozygotes. In-silico tool predicts 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. T665R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.056 (307 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3546 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.03
• Publications: 39 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=0.0026575327).
• BP6: Variant 12-862125-C-T is Benign according to our data. Variant chr12-862125-C-T is described in ClinVar as Benign. ClinVar VariationId is 137924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.078 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.1994C>T	p.Thr665Ile	missense	Exon 8 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.1994C>T	p.Thr665Ile	missense	Exon 8 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.1994C>T	p.Thr665Ile	missense	Exon 8 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.1994C>T	p.Thr665Ile	missense	Exon 8 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.1994C>T	p.Thr665Ile	missense	Exon 8 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.1994C>T	p.Thr665Ile	missense	Exon 8 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8471 AN: 152050 Hom.: 308 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0668

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.0845

Gnomad SAS AF: 0.0301

Gnomad FIN AF: 0.0811

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0732

Gnomad OTH AF: 0.0636

GnomAD2 exomes AF: 0.0661 AC: 16604 AN: 251344 AF XY: 0.0656

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0741

Gnomad ASJ exome AF: 0.0826

Gnomad EAS exome AF: 0.0928

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0717

Gnomad OTH exome AF: 0.0820

GnomAD4 exome AF: 0.0670 AC: 97886 AN: 1461794 Hom.: 3546 Cov.: 32 AF XY: 0.0665 AC XY: 48390 AN XY: 727202

African (AFR) AF: 0.0110 AC: 369 AN: 33476

American (AMR) AF: 0.0750 AC: 3355 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 2216 AN: 26134

East Asian (EAS) AF: 0.0797 AC: 3164 AN: 39698

South Asian (SAS) AF: 0.0272 AC: 2344 AN: 86258

European-Finnish (FIN) AF: 0.0828 AC: 4425 AN: 53410

Middle Eastern (MID) AF: 0.106 AC: 609 AN: 5766

European-Non Finnish (NFE) AF: 0.0696 AC: 77383 AN: 1111938

Other (OTH) AF: 0.0666 AC: 4021 AN: 60394

GnomAD4 genome AF: 0.0556 AC: 8463 AN: 152168 Hom.: 307 Cov.: 32 AF XY: 0.0552 AC XY: 4107 AN XY: 74374

African (AFR) AF: 0.0132 AC: 548 AN: 41522

American (AMR) AF: 0.0668 AC: 1020 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.0845 AC: 438 AN: 5182

South Asian (SAS) AF: 0.0295 AC: 142 AN: 4812

European-Finnish (FIN) AF: 0.0811 AC: 859 AN: 10588

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0732 AC: 4978 AN: 68000

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0701 Hom.: 1809

Bravo AF: 0.0547

TwinsUK AF: 0.0742 AC: 275

ALSPAC AF: 0.0708 AC: 273

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.0753 AC: 648

ExAC AF: 0.0639 AC: 7756

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.0853

EpiControl AF: 0.0812

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (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	Pathogenic	0.85
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.34	B
Vest4		0.52
MPC		0.13
ClinPred		0.030	T
GERP RS		5.9
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.16
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2286007; hg19: chr12-971291; COSMIC: COSV60041888; COSMIC: COSV60041888;