12-753541-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_213655.5(WNK1):c.-25C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00906 in 1,611,392 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (75 hom.)
• Consequence: WNK1 NM_213655.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.616

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-753541-C-G is Benign according to our data. Variant chr12-753541-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 310535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.-25C>G		5_prime_UTR_variant	1/28	ENST00000315939.11
WNK1	NM_213655.5	c.-25C>G		5_prime_UTR_variant	1/28	ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.-25C>G		5_prime_UTR_variant	1/28	1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.-25C>G		5_prime_UTR_variant	1/28	5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.00670 AC: 1020 AN: 152196 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00753 AC: 1799 AN: 238868 Hom.: 13 AF XY: 0.00752 AC XY: 988 AN XY: 131430

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.000615

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.000820

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00630

GnomAD4 exome AF: 0.00931 AC: 13578 AN: 1459078 Hom.: 75 Cov.: 32 AF XY: 0.00898 AC XY: 6518 AN XY: 725782

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00783

GnomAD4 genome AF: 0.00670 AC: 1020 AN: 152314 Hom.: 6 Cov.: 33 AF XY: 0.00669 AC XY: 498 AN XY: 74466

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.00992

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00556

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudohypoaldosteronism type 2C Benign:1

Benign, 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 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	16
Dann	Benign	0.61
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: rs72647367; hg19: chr12-862707;