12-885406-TAGC-T

Variant names:

• chr12-885406-TAGC-T
• rs72650732
• NM_213655.5:c.5361_5363delCAG

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_018979.4(WNK1):​c.4605_4607delCAG​(p.Ser1536del) variant causes a disruptive 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_018979.4 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_018979.4. 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].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00148 (225/152316) while in subpopulation AMR AF= 0.00242 (37/15298). AF 95% confidence interval is 0.0018. There are 0 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.5361_5363delCAG	p.Ser1788del	disruptive_inframe_deletion	Exon 19 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.4605_4607delCAG	p.Ser1536del	disruptive_inframe_deletion	Exon 19 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.5361_5363delCAG	p.Ser1788del	disruptive_inframe_deletion	Exon 19 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.4605_4607delCAG	p.Ser1536del	disruptive_inframe_deletion	Exon 19 of 28	1	NM_018979.4	ENSP00000313059.6

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 18, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WNK1: PM4:Supporting, BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Apr 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: WNK1 c.4605_4607delCAG (p.Ser1536del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0023 in 250998 control chromosomes, predominantly at a frequency of 0.0057 within the Latino subpopulation in the gnomAD database, including 3 homozygotes. To our knowledge, no occurrence of c.4605_4607delCAG in individuals affected with Neuropathy, Hereditary Sensory And Autonomic, Type 2A and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 310831). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary sensory and autonomic neuropathy type 2 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 02, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoaldosteronism type 2A Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;