chr12-862151-A-G

Position:

• chr12-862151-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213655.5(WNK1):​c.2020A>G​(p.Thr674Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00163 in 1,614,104 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T674I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0075 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (15 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.17

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WNK1. . Gene score misZ 2.1626 (greater than the threshold 3.09). Trascript score misZ 4.7 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory and autonomic, type 2A, hereditary sensory and autonomic neuropathy type 2, pseudohypoaldosteronism type 2C.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0033073127).
• BP6: Variant 12-862151-A-G is Benign according to our data. Variant chr12-862151-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 310742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-862151-A-G is described in Lovd as [Benign]. Variant chr12-862151-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (1141/152258) while in subpopulation AFR AF= 0.0241 (1002/41550). AF 95% confidence interval is 0.0229. There are 13 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNK1	NM_213655.5	c.2020A>G	p.Thr674Ala	missense_variant	8/28	ENST00000340908.9
WNK1	NM_018979.4	c.2020A>G	p.Thr674Ala	missense_variant	8/28	ENST00000315939.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNK1	ENST00000340908.9	c.2020A>G	p.Thr674Ala	missense_variant	8/28	5	NM_213655.5	A2
WNK1	ENST00000315939.11	c.2020A>G	p.Thr674Ala	missense_variant	8/28	1	NM_018979.4	P2

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1139 AN: 152140 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00232 AC: 582 AN: 251376 Hom.: 3 AF XY: 0.00187 AC XY: 254 AN XY: 135856

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00102 AC: 1486 AN: 1461846 Hom.: 15 Cov.: 32 AF XY: 0.000924 AC XY: 672 AN XY: 727228

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00589

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.00749 AC: 1141 AN: 152258 Hom.: 13 Cov.: 32 AF XY: 0.00768 AC XY: 572 AN XY: 74440

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.00478

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00216 Hom.: 8

Bravo AF: 0.00830

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Dec 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 03, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;T;.;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;D;T
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;M;M;M
MutationTaster	Benign	0.65	D;D;D;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D;D;D;.;D
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;.;D
Sift4G	Uncertain	0.039	D;.;D;T;D
Polyphen		0.17	B;.;B;.;.
Vest4		0.14
MVP		0.15
MPC		0.12
ClinPred		0.038	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.31

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: rs11833299; hg19: chr12-971317; COSMIC: COSV99049285; COSMIC: COSV99049285;