rs141971833

Positions:

• chr12-883559-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_213655.5(WNK1):​c.4410A>G​(p.Ser1470=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,614,212 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (82 hom.)
• Consequence: WNK1 NM_213655.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.88

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=-0.58).
• BP6: Variant 12-883559-A-G is Benign according to our data. Variant chr12-883559-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 310820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-883559-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00395 (601/152342) while in subpopulation SAS AF= 0.0319 (154/4822). AF 95% confidence interval is 0.0278. There are 4 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.4410A>G	p.Ser1470=	synonymous_variant	16/28	ENST00000340908.9
WNK1	NM_018979.4	c.3654A>G	p.Ser1218=	synonymous_variant	16/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.4410A>G	p.Ser1470=	synonymous_variant	16/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.3654A>G	p.Ser1218=	synonymous_variant	16/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 602 AN: 152224 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00928

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00465 AC: 1170 AN: 251406 Hom.: 26 AF XY: 0.00560 AC XY: 761 AN XY: 135898

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0281

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00237 AC: 3461 AN: 1461870 Hom.: 82 Cov.: 33 AF XY: 0.00309 AC XY: 2246 AN XY: 727236

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0276

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152342 Hom.: 4 Cov.: 33 AF XY: 0.00428 AC XY: 319 AN XY: 74492

Gnomad4 AFR AF: 0.00926

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0319

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00211 Hom.: 0

Bravo AF: 0.00377

Asia WGS AF: 0.0120 AC: 44 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.1
DANN	Benign	0.73

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: rs141971833; hg19: chr12-992725; COSMIC: COSV104411009; COSMIC: COSV104411009;