rs56015776

chr12-879667-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_018979.4(WNK1):c.2468A>G(p.His823Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00063 in 1,613,338 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.44

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, WNK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.086987585).
• BP6: Variant 12-879667-A-G is Benign according to our data. Variant chr12-879667-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 310749.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_018979.4	c.2468A>G	p.His823Arg	missense_variant	11/28	ENST00000315939.11
WNK1	NM_213655.5	c.3867+1306A>G		intron_variant		ENST00000340908.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000315939.11	c.2468A>G	p.His823Arg	missense_variant	11/28	1	NM_018979.4	P2
WNK1	ENST00000340908.9	c.3867+1306A>G		intron_variant		5	NM_213655.5	A2

Frequencies

GnomAD3 genomes AF: 0.000410 AC: 62 AN: 151342 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000560

Gnomad OTH AF: 0.000965

GnomAD3 exomes AF: 0.000374 AC: 94 AN: 251458 Hom.: 0 AF XY: 0.000390 AC XY: 53 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000653 AC: 954 AN: 1461880 Hom.: 1 Cov.: 35 AF XY: 0.000615 AC XY: 447 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000808

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000409 AC: 62 AN: 151458 Hom.: 0 Cov.: 29 AF XY: 0.000189 AC XY: 14 AN XY: 73984

Gnomad4 AFR AF: 0.0000970

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.000560

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000592 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 03, 2020

This sequence change replaces histidine with arginine at codon 823 of the WNK1 protein (p.His823Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs56015776, ExAC 0.06%) but has not been reported in the literature in individuals with a WNK1-related disease. ClinVar contains an entry for this variant (Variation ID: 310749). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2016

- -

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
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Benign	0.95
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.80	D;D;D;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.1	D;N;D
REVEL	Benign	0.097
Sift	Pathogenic	0.0	D;D;D
Polyphen		0.77	.;P;.
Vest4		0.71
MVP		0.19
MPC		0.34
ClinPred		0.19	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20

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: rs56015776; hg19: chr12-988833;