rs72650715

chr12-881682-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_213655.5(WNK1):c.3868-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,604,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: WNK1 NM_213655.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001232
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.160

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-881682-C-T is Benign according to our data. Variant chr12-881682-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 310814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.3112-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000315939.11
WNK1	NM_213655.5	c.3868-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.3112-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.3868-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000963 AC: 242 AN: 251426 Hom.: 0 AF XY: 0.000920 AC XY: 125 AN XY: 135892

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00186 AC: 2705 AN: 1452744 Hom.: 4 Cov.: 27 AF XY: 0.00181 AC XY: 1307 AN XY: 723480

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00173

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000337

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152224 Hom.: 0 Cov.: 31 AF XY: 0.000900 AC XY: 67 AN XY: 74414

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -

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. -

Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.4
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.010		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: rs72650715; hg19: chr12-990848; COSMIC: COSV104411255; COSMIC: COSV104411255;