12-906303-G-C

Variant names:

• chr12-906303-G-C
• rs2286028
• NM_213655.5:c.7400-1544G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_018979.4(WNK1):​c.6644-1544G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 984,976 control chromosomes in the GnomAD database, including 18,242 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (2039 hom., cov: 31)
  • Exomes 𝑓: 0.19 (16203 hom.)
• Consequence: WNK1 NM_018979.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.745
• Publications: 11 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.201 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.7400-1544G>C		intron	N/A	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.6644-1544G>C		intron	N/A	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.7424-1544G>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.7400-1544G>C		intron	N/A	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.6644-1544G>C		intron	N/A	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.7997-1544G>C		intron	N/A	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22011 AN: 151916 Hom.: 2037 Cov.: 31

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0874

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.193 AC: 161012 AN: 832942 Hom.: 16203 Cov.: 28 AF XY: 0.192 AC XY: 73952 AN XY: 384646

African (AFR) AF: 0.0188 AC: 296 AN: 15784

American (AMR) AF: 0.261 AC: 257 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 522 AN: 5152

East Asian (EAS) AF: 0.0752 AC: 273 AN: 3630

South Asian (SAS) AF: 0.145 AC: 2384 AN: 16460

European-Finnish (FIN) AF: 0.199 AC: 55 AN: 276

Middle Eastern (MID) AF: 0.0729 AC: 118 AN: 1618

European-Non Finnish (NFE) AF: 0.200 AC: 152454 AN: 761746

Other (OTH) AF: 0.170 AC: 4653 AN: 27292

GnomAD4 genome AF: 0.145 AC: 22014 AN: 152034 Hom.: 2039 Cov.: 31 AF XY: 0.146 AC XY: 10860 AN XY: 74290

African (AFR) AF: 0.0363 AC: 1506 AN: 41504

American (AMR) AF: 0.207 AC: 3153 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3470

East Asian (EAS) AF: 0.0872 AC: 450 AN: 5158

South Asian (SAS) AF: 0.134 AC: 643 AN: 4806

European-Finnish (FIN) AF: 0.192 AC: 2025 AN: 10546

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13465 AN: 67978

Other (OTH) AF: 0.130 AC: 275 AN: 2108

Alfa AF: 0.108 Hom.: 202

Bravo AF: 0.141

Asia WGS AF: 0.0970 AC: 338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.69
PhyloP100		0.74
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: rs2286028; hg19: chr12-1015469;