chr12-780667-A-G

Variant names:

• chr12-780667-A-G
• rs11608756
• NM_213655.5:c.759+26343A>G

Variant summary

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

The NM_213655.5(WNK1):​c.759+26343A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 152,100 control chromosomes in the GnomAD database, including 24,964 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 0.57 (24964 hom., cov: 33)
• Consequence: WNK1 NM_213655.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213655.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	NM_213655.5	MANE Plus Clinical	c.759+26343A>G		intron	N/A	NP_998820.3
	WNK1	NM_018979.4	MANE Select	c.759+26343A>G		intron	N/A	NP_061852.3
	WNK1	NM_001184985.2		c.759+26343A>G		intron	N/A	NP_001171914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.759+26343A>G		intron	N/A	ENSP00000341292.5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.759+26343A>G		intron	N/A	ENSP00000313059.6
	WNK1	ENST00000530271.6	TSL:1	c.759+26343A>G		intron	N/A	ENSP00000433548.3

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86388 AN: 151980 Hom.: 24951 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.573

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

GnomAD4 genome AF: 0.568 AC: 86442 AN: 152100 Hom.: 24964 Cov.: 33 AF XY: 0.568 AC XY: 42213 AN XY: 74356

African (AFR) AF: 0.496 AC: 20558 AN: 41482

American (AMR) AF: 0.576 AC: 8803 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1756 AN: 3470

East Asian (EAS) AF: 0.808 AC: 4197 AN: 5192

South Asian (SAS) AF: 0.561 AC: 2707 AN: 4824

European-Finnish (FIN) AF: 0.533 AC: 5632 AN: 10566

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40829 AN: 67974

Other (OTH) AF: 0.570 AC: 1206 AN: 2114

Alfa AF: 0.593 Hom.: 100217

Bravo AF: 0.571

Asia WGS AF: 0.637 AC: 2213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.89
PhyloP100		2.6
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: rs11608756; hg19: chr12-889833;