12-813797-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The ENST00000315939.11(WNK1):​c.915G>A​(p.Thr305=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000709 in 1,613,790 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T305T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00072 ( 5 hom. )

Consequence

WNK1
ENST00000315939.11 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.113
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
Variant 12-813797-G-A is Benign according to our data. Variant chr12-813797-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 310670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.113 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WNK1NM_213655.5 linkuse as main transcriptc.915G>A p.Thr305= synonymous_variant 2/28 ENST00000340908.9 NP_998820.3
WNK1NM_018979.4 linkuse as main transcriptc.915G>A p.Thr305= synonymous_variant 2/28 ENST00000315939.11 NP_061852.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNK1ENST00000340908.9 linkuse as main transcriptc.915G>A p.Thr305= synonymous_variant 2/285 NM_213655.5 ENSP00000341292 A2Q9H4A3-5
WNK1ENST00000315939.11 linkuse as main transcriptc.915G>A p.Thr305= synonymous_variant 2/281 NM_018979.4 ENSP00000313059 P2Q9H4A3-1

Frequencies

GnomAD3 genomes
AF:
0.000592
AC:
90
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00403
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00414
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000559
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000689
AC:
173
AN:
251126
Hom.:
0
AF XY:
0.000862
AC XY:
117
AN XY:
135754
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00397
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00150
Gnomad FIN exome
AF:
0.000463
Gnomad NFE exome
AF:
0.000564
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000721
AC:
1054
AN:
1461520
Hom.:
5
Cov.:
32
AF XY:
0.000789
AC XY:
574
AN XY:
727072
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000291
Gnomad4 ASJ exome
AF:
0.00310
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00139
Gnomad4 FIN exome
AF:
0.000225
Gnomad4 NFE exome
AF:
0.000711
Gnomad4 OTH exome
AF:
0.000547
GnomAD4 genome
AF:
0.000591
AC:
90
AN:
152270
Hom.:
0
Cov.:
32
AF XY:
0.000712
AC XY:
53
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00403
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00415
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.000559
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000747
Hom.:
0
Bravo
AF:
0.000427
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000534

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024WNK1: BP4, BP7 -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 18, 2023- -
Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 10, 2024- -
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 09, 2021- -
Pseudohypoaldosteronism type 2C Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
-0.55
CADD
Benign
8.9
DANN
Benign
0.73
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72648609; hg19: chr12-922963; API