12-906007-G-A

Variant names:

• chr12-906007-G-A
• rs2286026
• NM_213655.5:c.7400-1840G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_213655.5(WNK1):​c.7400-1840G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 151,936 control chromosomes in the GnomAD database, including 15,827 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 0.45 (15827 hom., cov: 31)
• Consequence: WNK1 NM_213655.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.785
• Publications: 7 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), ClinGen, G2P, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.7400-1840G>A		intron_variant	Intron 26 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.6644-1840G>A		intron_variant	Intron 26 of 27	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.7400-1840G>A		intron_variant	Intron 26 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.6644-1840G>A		intron_variant	Intron 26 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67888 AN: 151818 Hom.: 15806 Cov.: 31

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.465

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67958 AN: 151936 Hom.: 15827 Cov.: 31 AF XY: 0.443 AC XY: 32900 AN XY: 74278

African (AFR) AF: 0.557 AC: 23061 AN: 41408

American (AMR) AF: 0.452 AC: 6914 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1594 AN: 3466

East Asian (EAS) AF: 0.287 AC: 1482 AN: 5160

South Asian (SAS) AF: 0.506 AC: 2436 AN: 4816

European-Finnish (FIN) AF: 0.299 AC: 3149 AN: 10548

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27913 AN: 67938

Other (OTH) AF: 0.468 AC: 987 AN: 2110

Alfa AF: 0.277 Hom.: 657

Bravo AF: 0.460

Asia WGS AF: 0.439 AC: 1526 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.69
PhyloP100		0.79
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: rs2286026; hg19: chr12-1015173;