12-753114-G-A

Position:

• chr12-753114-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018979.4(WNK1):​c.-452G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 153,078 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (210 hom., cov: 31)
  • Exomes 𝑓: 0.048 (1 hom.)
• Consequence: WNK1 NM_018979.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.424

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-753114-G-A is Benign according to our data. Variant chr12-753114-G-A is described in ClinVar as [Benign]. Clinvar id is 310519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5	c.-452G>A		5_prime_UTR_variant	1/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.-452G>A		5_prime_UTR_variant	1/28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908	c.-452G>A		5_prime_UTR_variant	1/28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939	c.-452G>A		5_prime_UTR_variant	1/28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6927 AN: 151530 Hom.: 210 Cov.: 31

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0135

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.0936

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0552

GnomAD4 exome AF: 0.0479 AC: 69 AN: 1440 Hom.: 1 Cov.: 0 AF XY: 0.0395 AC XY: 31 AN XY: 784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.0690

Gnomad4 EAS exome AF: 0.0714

Gnomad4 SAS exome AF: 0.0238

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.0518

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0456 AC: 6920 AN: 151638 Hom.: 210 Cov.: 31 AF XY: 0.0459 AC XY: 3404 AN XY: 74114

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.0552

Gnomad4 ASJ AF: 0.0651

Gnomad4 EAS AF: 0.0937

Gnomad4 SAS AF: 0.0259

Gnomad4 FIN AF: 0.0775

Gnomad4 NFE AF: 0.0570

Gnomad4 OTH AF: 0.0547

Alfa AF: 0.0208 Hom.: 7

Bravo AF: 0.0444

Asia WGS AF: 0.0330 AC: 112 AN: 3394

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pseudohypoaldosteronism type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs118007973; hg19: chr12-862280;