12-753444-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_213655.5(WNK1):c.-122C>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 0.0014 in 1,339,280 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00099 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (14 hom.)
• Consequence: WNK1 NM_213655.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.345

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 12-753444-C-T is Benign according to our data. Variant chr12-753444-C-T is described in ClinVar as [Benign]. Clinvar id is 310532.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.-122C>T		5_prime_UTR_variant	1/28	ENST00000315939.11
WNK1	NM_213655.5	c.-122C>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.-122C>T		5_prime_UTR_variant	1/28	1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.-122C>T		5_prime_UTR_variant	1/28	5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152156 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00146 AC: 1730 AN: 1187016 Hom.: 14 Cov.: 17 AF XY: 0.00177 AC XY: 1043 AN XY: 589262

Gnomad4 AFR exome AF: 0.000110

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00904

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00904

Gnomad4 FIN exome AF: 0.0000531

Gnomad4 NFE exome AF: 0.000789

Gnomad4 OTH exome AF: 0.00170

GnomAD4 genome AF: 0.000992 AC: 151 AN: 152264 Hom.: 2 Cov.: 31 AF XY: 0.00105 AC XY: 78 AN XY: 74458

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000900 Hom.: 0

Bravo AF: 0.000812

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.64
Cadd	Benign	14
Dann	Benign	0.97
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: rs538911254; hg19: chr12-862610;