rs2301880

Variant names:

• chr12-894671-C-T
• rs2301880
• NM_213655.5:c.6339+36C>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.5583+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,586,762 control chromosomes in the GnomAD database, including 47,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4743 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42519 hom.)
• Consequence: WNK1 NM_018979.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.836
• Publications: 14 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 (BayesDel_noAF=-0.94).
• BP6: Variant 12-894671-C-T is Benign according to our data. Variant chr12-894671-C-T is described in ClinVar as Benign. ClinVar VariationId is 674135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 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.6339+36C>T		intron	N/A	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.5583+36C>T		intron	N/A	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.6363+36C>T		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.6339+36C>T		intron	N/A	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.5583+36C>T		intron	N/A	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.6822+36C>T		intron	N/A	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37669 AN: 151916 Hom.: 4738 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.236 AC: 59206 AN: 251250 AF XY: 0.236

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.242 AC: 347147 AN: 1434730 Hom.: 42519 Cov.: 26 AF XY: 0.242 AC XY: 173385 AN XY: 715544

African (AFR) AF: 0.283 AC: 9300 AN: 32884

American (AMR) AF: 0.222 AC: 9907 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7869 AN: 25950

East Asian (EAS) AF: 0.213 AC: 8434 AN: 39510

South Asian (SAS) AF: 0.241 AC: 20637 AN: 85670

European-Finnish (FIN) AF: 0.195 AC: 10392 AN: 53330

Middle Eastern (MID) AF: 0.319 AC: 1826 AN: 5716

European-Non Finnish (NFE) AF: 0.243 AC: 264229 AN: 1087544

Other (OTH) AF: 0.245 AC: 14553 AN: 59458

GnomAD4 genome AF: 0.248 AC: 37703 AN: 152032 Hom.: 4743 Cov.: 32 AF XY: 0.245 AC XY: 18223 AN XY: 74292

African (AFR) AF: 0.275 AC: 11385 AN: 41474

American (AMR) AF: 0.231 AC: 3527 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1081 AN: 3466

East Asian (EAS) AF: 0.196 AC: 1012 AN: 5174

South Asian (SAS) AF: 0.254 AC: 1222 AN: 4818

European-Finnish (FIN) AF: 0.187 AC: 1981 AN: 10574

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16714 AN: 67936

Other (OTH) AF: 0.270 AC: 570 AN: 2110

Alfa AF: 0.252 Hom.: 1156

Bravo AF: 0.252

Asia WGS AF: 0.255 AC: 885 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2A (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
BayesDel_noAF	Benign	-0.94
CADD	Benign	8.1
DANN	Benign	0.63
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism (auto)

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: rs2301880; hg19: chr12-1003837; COSMIC: COSV104411037; COSMIC: COSV104411037;