chr12-753198-G-T

Position:

• chr12-753198-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_213655.5(WNK1):​c.-368G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 188,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00090 (0 hom.)
• Consequence: WNK1 NM_213655.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.260

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.-368G>T		5_prime_UTR_variant	1/28	ENST00000315939.11
WNK1	NM_213655.5	c.-368G>T		5_prime_UTR_variant	1/28	ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.-368G>T		5_prime_UTR_variant	1/28	1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.-368G>T		5_prime_UTR_variant	1/28	5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.000712 AC: 107 AN: 150234 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000376

Gnomad OTH AF: 0.000483

GnomAD4 exome AF: 0.000898 AC: 34 AN: 37862 Hom.: 0 Cov.: 0 AF XY: 0.000730 AC XY: 14 AN XY: 19178

Gnomad4 AFR exome AF: 0.000752

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00675

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000475

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.000712 AC: 107 AN: 150344 Hom.: 0 Cov.: 31 AF XY: 0.000748 AC XY: 55 AN XY: 73546

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000376

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000684

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pseudohypoaldosteronism type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.2
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886049859; hg19: chr12-862364;