chr12-780736-T-G

Variant names:

• chr12-780736-T-G
• rs11064524
• NM_213655.5:c.759+26412T>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+26412T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,192 control chromosomes in the GnomAD database, including 3,969 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 0.22 (3969 hom., cov: 33)
• Consequence: WNK1 NM_213655.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 12 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=-0.42).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.759+26412T>G		intron_variant	Intron 1 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.759+26412T>G		intron_variant	Intron 1 of 27	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.759+26412T>G		intron_variant	Intron 1 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.759+26412T>G		intron_variant	Intron 1 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33680 AN: 152074 Hom.: 3963 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.221

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

GnomAD4 genome AF: 0.221 AC: 33700 AN: 152192 Hom.: 3969 Cov.: 33 AF XY: 0.223 AC XY: 16613 AN XY: 74412

African (AFR) AF: 0.154 AC: 6400 AN: 41522

American (AMR) AF: 0.288 AC: 4397 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3472

East Asian (EAS) AF: 0.316 AC: 1638 AN: 5180

South Asian (SAS) AF: 0.217 AC: 1050 AN: 4830

European-Finnish (FIN) AF: 0.216 AC: 2291 AN: 10588

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16573 AN: 68002

Other (OTH) AF: 0.220 AC: 465 AN: 2116

Alfa AF: 0.238 Hom.: 19930

Bravo AF: 0.226

Asia WGS AF: 0.237 AC: 824 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.81
PhyloP100		3.0
Mutation Taster		=93/7	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: rs11064524; hg19: chr12-889902;