12-781859-A-C

Variant names:

• chr12-781859-A-C
• rs11064527
• NM_213655.5:c.759+27535A>C

Variant summary

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

The NM_213655.5(WNK1):​c.759+27535A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 151,974 control chromosomes in the GnomAD database, including 1,686 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 0.13 (1686 hom., cov: 32)
• Consequence: WNK1 NM_213655.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.759+27535A>C		intron_variant	Intron 1 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.759+27535A>C		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+27535A>C		intron_variant	Intron 1 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.759+27535A>C		intron_variant	Intron 1 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19974 AN: 151856 Hom.: 1686 Cov.: 32

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.131 AC: 19979 AN: 151974 Hom.: 1686 Cov.: 32 AF XY: 0.135 AC XY: 10042 AN XY: 74282

African (AFR) AF: 0.0376 AC: 1562 AN: 41490

American (AMR) AF: 0.106 AC: 1619 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3470

East Asian (EAS) AF: 0.0638 AC: 331 AN: 5186

South Asian (SAS) AF: 0.175 AC: 842 AN: 4820

European-Finnish (FIN) AF: 0.276 AC: 2899 AN: 10504

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11653 AN: 67936

Other (OTH) AF: 0.129 AC: 272 AN: 2106

Alfa AF: 0.0816 Hom.: 113

Bravo AF: 0.113

Asia WGS AF: 0.108 AC: 375 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.64
PhyloP100		-0.066
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: rs11064527; hg19: chr12-891025;