rs61736905

Variant names:

• chr12-862212-T-C
• rs61736905
• NM_213655.5:c.2081T>C

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.2081T>C​(p.Ile694Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,614,092 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (44 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.99
• Publications: 2 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=0.001639992).
• BP6: Variant 12-862212-T-C is Benign according to our data. Variant chr12-862212-T-C is described in ClinVar as Benign. ClinVar VariationId is 310744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 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.2081T>C	p.Ile694Thr	missense	Exon 8 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.2081T>C	p.Ile694Thr	missense	Exon 8 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.2081T>C	p.Ile694Thr	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.2081T>C	p.Ile694Thr	missense	Exon 8 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.2081T>C	p.Ile694Thr	missense	Exon 8 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.2081T>C	p.Ile694Thr	missense	Exon 8 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2303 AN: 152140 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00409 AC: 1028 AN: 251330 AF XY: 0.00304

Gnomad AFR exome AF: 0.0511

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00170 AC: 2488 AN: 1461834 Hom.: 44 Cov.: 32 AF XY: 0.00149 AC XY: 1080 AN XY: 727228

African (AFR) AF: 0.0524 AC: 1755 AN: 33476

American (AMR) AF: 0.00414 AC: 185 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5766

European-Non Finnish (NFE) AF: 0.000231 AC: 257 AN: 1111966

Other (OTH) AF: 0.00412 AC: 249 AN: 60396

GnomAD4 genome AF: 0.0151 AC: 2303 AN: 152258 Hom.: 59 Cov.: 32 AF XY: 0.0148 AC XY: 1103 AN XY: 74442

African (AFR) AF: 0.0521 AC: 2164 AN: 41548

American (AMR) AF: 0.00602 AC: 92 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68032

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00689 Hom.: 18

Bravo AF: 0.0175

ESP6500AA AF: 0.0495 AC: 218

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00473 AC: 574

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	0.10
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.27
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.9	N
PhyloP100		3.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	0.46	T
Polyphen		0.050	B
Vest4		0.053
MVP		0.043
MPC		0.15
ClinPred		0.00062	T
GERP RS		5.0
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.019
gMVP		0.020
Mutation Taster		=94/6	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: rs61736905; hg19: chr12-971378; COSMIC: COSV104411134;