rs146586443

chr12-886025-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6_Moderate

The NM_213655.5(WNK1):c.5977A>G(p.Thr1993Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000382 in 1,598,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.44

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 -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, WNK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.013862491).
• BP6: Variant 12-886025-A-G is Benign according to our data. Variant chr12-886025-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 568784.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.5977A>G	p.Thr1993Ala	missense_variant	19/28	ENST00000340908.9
WNK1	NM_018979.4	c.5221A>G	p.Thr1741Ala	missense_variant	19/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.5977A>G	p.Thr1993Ala	missense_variant	19/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.5221A>G	p.Thr1741Ala	missense_variant	19/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000721 AC: 17 AN: 235648 Hom.: 0 AF XY: 0.0000392 AC XY: 5 AN XY: 127440

Gnomad AFR exome AF: 0.000999

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 24 AN: 1446472 Hom.: 0 Cov.: 36 AF XY: 0.00000834 AC XY: 6 AN XY: 719336

Gnomad4 AFR exome AF: 0.000646

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74476

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.24
Dann	Benign	0.24
DEOGEN2	Benign	0.069	T;.;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.58	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.030	N;.;N;.;N
REVEL	Benign	0.070
Sift	Benign	0.67	T;.;T;.;T
Sift4G	Benign	0.99	T;.;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.037
MVP		0.082
MPC		0.12
ClinPred		0.0068	T
GERP RS		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		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: rs146586443; hg19: chr12-995191;