rs10849577

chr12-884848-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_213655.5(WNK1):c.4800C>T(p.Thr1600=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,613,942 control chromosomes in the GnomAD database, including 18,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1468 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16805 hom.)
• Consequence: WNK1 NM_213655.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0490

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-884848-C-T is Benign according to our data. Variant chr12-884848-C-T is described in ClinVar as [Benign]. Clinvar id is 137926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-884848-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.049 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.4800C>T	p.Thr1600=	synonymous_variant	19/28	ENST00000340908.9
WNK1	NM_018979.4	c.4044C>T	p.Thr1348=	synonymous_variant	19/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.4800C>T	p.Thr1600=	synonymous_variant	19/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.4044C>T	p.Thr1348=	synonymous_variant	19/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19293 AN: 151970 Hom.: 1465 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.156 AC: 39135 AN: 251332 Hom.: 3432 AF XY: 0.159 AC XY: 21633 AN XY: 135844

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.148 AC: 215628 AN: 1461854 Hom.: 16805 Cov.: 80 AF XY: 0.149 AC XY: 108363 AN XY: 727234

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.127 AC: 19302 AN: 152088 Hom.: 1468 Cov.: 32 AF XY: 0.132 AC XY: 9803 AN XY: 74342

Gnomad4 AFR AF: 0.0495

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.128

Alfa AF: 0.136 Hom.: 765

Bravo AF: 0.112

Asia WGS AF: 0.154 AC: 538 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.150

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Neuropathy, hereditary sensory and autonomic, type 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.9
Dann	Benign	0.40
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: rs10849577; hg19: chr12-994014; COSMIC: COSV60028295; COSMIC: COSV60028295;