rs72650732

chr12-885406-TAGC-Tchr12-885406-TAGC-TAGCAGC

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_213655.5(WNK1):c.5361_5363del(p.Ser1788del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,742 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: WNK1 NM_213655.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.96

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 -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_213655.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 12-885406-TAGC-T is Benign according to our data. Variant chr12-885406-TAGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 310831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-885406-TAGC-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.4605_4607del	p.Ser1536del	inframe_deletion	19/28	ENST00000315939.11
WNK1	NM_213655.5	c.5361_5363del	p.Ser1788del	inframe_deletion	19/28	ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.4605_4607del	p.Ser1536del	inframe_deletion	19/28	1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.5361_5363del	p.Ser1788del	inframe_deletion	19/28	5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00226 AC: 568 AN: 250998 Hom.: 5 AF XY: 0.00206 AC XY: 279 AN XY: 135690

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00569

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00694

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00136 AC: 1988 AN: 1461426 Hom.: 7 AF XY: 0.00139 AC XY: 1012 AN XY: 727046

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00552

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00759

Gnomad4 NFE exome AF: 0.000972

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74486

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00753

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.00129

EpiCase AF: 0.00120

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	Mar 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	WNK1: PM4:Supporting, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hereditary sensory and autonomic neuropathy type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Pseudohypoaldosteronism type 2A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs72650732; hg19: chr12-994572;