12-894591-GCAACTAGTT-G

Position:

• chr12-894591-GCAACTAGTT-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_018979.4(WNK1):​c.5542_5550delACTAGTTCA​(p.Thr1848_Ser1850del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,613,868 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (22 hom.)
• Consequence: WNK1 NM_018979.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.50

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.

• PM4: Nonframeshift variant in NON repetitive region in NM_018979.4.
• BP6: Variant 12-894591-GCAACTAGTT-G is Benign according to our data. Variant chr12-894591-GCAACTAGTT-G is described in ClinVar as [Likely_benign]. Clinvar id is 471200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-894591-GCAACTAGTT-G is described in Lovd as [Likely_benign]. Variant chr12-894591-GCAACTAGTT-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5	c.6298_6306delACTAGTTCA	p.Thr2100_Ser2102del	conservative_inframe_deletion	23/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.5542_5550delACTAGTTCA	p.Thr1848_Ser1850del	conservative_inframe_deletion	23/28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.6298_6306delACTAGTTCA	p.Thr2100_Ser2102del	conservative_inframe_deletion	23/28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.5542_5550delACTAGTTCA	p.Thr1848_Ser1850del	conservative_inframe_deletion	23/28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00305 AC: 766 AN: 251414 Hom.: 4 AF XY: 0.00355 AC XY: 482 AN XY: 135876

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00954

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00254 AC: 3709 AN: 1461566 Hom.: 22 AF XY: 0.00283 AC XY: 2059 AN XY: 727096

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00959

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74472

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00270

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000721 Hom.: 0

Bravo AF: 0.00187

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	WNK1: PM4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 30, 2020	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 12, 2021	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs544395150; hg19: chr12-1003757;