12-881746-A-C

Variant names:

• chr12-881746-A-C
• rs956868
• NM_213655.5:c.3922A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001184985.2(WNK1):​c.3946A>C​(p.Thr1316Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,940 control chromosomes in the GnomAD database, including 575,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1316T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.84 (53881 hom., cov: 31)
  • Exomes 𝑓: 0.84 (521657 hom.)
• Consequence: WNK1 NM_001184985.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0690
• Publications: 58 publications found

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]

WNK1 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• pseudohypoaldosteronism type 2C

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.2372313E-7).
• BP6: Variant 12-881746-A-C is Benign according to our data. Variant chr12-881746-A-C is described in ClinVar as Benign. ClinVar VariationId is 261070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184985.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	NM_213655.5	MANE Plus Clinical	c.3922A>C	p.Thr1308Pro	missense	Exon 13 of 28	NP_998820.3
	WNK1	NM_018979.4	MANE Select	c.3166A>C	p.Thr1056Pro	missense	Exon 13 of 28	NP_061852.3
	WNK1	NM_001184985.2		c.3946A>C	p.Thr1316Pro	missense	Exon 13 of 28	NP_001171914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.3922A>C	p.Thr1308Pro	missense	Exon 13 of 28	ENSP00000341292.5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.3166A>C	p.Thr1056Pro	missense	Exon 13 of 28	ENSP00000313059.6
	WNK1	ENST00000530271.6	TSL:1	c.4405A>C	p.Thr1469Pro	missense	Exon 14 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127863 AN: 152010 Hom.: 53836 Cov.: 31

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.847

GnomAD2 exomes AF: 0.832 AC: 209232 AN: 251432 AF XY: 0.831

Gnomad AFR exome AF: 0.859

Gnomad AMR exome AF: 0.865

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.807

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.841

Gnomad OTH exome AF: 0.826

GnomAD4 exome AF: 0.844 AC: 1234188 AN: 1461812 Hom.: 521657 Cov.: 61 AF XY: 0.843 AC XY: 613179 AN XY: 727216

African (AFR) AF: 0.857 AC: 28683 AN: 33478

American (AMR) AF: 0.866 AC: 38713 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 22087 AN: 26136

East Asian (EAS) AF: 0.839 AC: 33323 AN: 39696

South Asian (SAS) AF: 0.823 AC: 70967 AN: 86258

European-Finnish (FIN) AF: 0.746 AC: 39825 AN: 53410

Middle Eastern (MID) AF: 0.768 AC: 4432 AN: 5768

European-Non Finnish (NFE) AF: 0.850 AC: 945586 AN: 1111950

Other (OTH) AF: 0.837 AC: 50572 AN: 60392

GnomAD4 genome AF: 0.841 AC: 127963 AN: 152128 Hom.: 53881 Cov.: 31 AF XY: 0.838 AC XY: 62286 AN XY: 74370

African (AFR) AF: 0.856 AC: 35490 AN: 41482

American (AMR) AF: 0.863 AC: 13202 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2929 AN: 3470

East Asian (EAS) AF: 0.817 AC: 4229 AN: 5178

South Asian (SAS) AF: 0.830 AC: 3998 AN: 4814

European-Finnish (FIN) AF: 0.735 AC: 7763 AN: 10564

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.847 AC: 57607 AN: 68008

Other (OTH) AF: 0.848 AC: 1793 AN: 2114

Alfa AF: 0.847 Hom.: 193009

Bravo AF: 0.851

TwinsUK AF: 0.856 AC: 3175

ALSPAC AF: 0.855 AC: 3296

ESP6500AA AF: 0.855 AC: 3768

ESP6500EA AF: 0.851 AC: 7321

ExAC AF: 0.831 AC: 100941

Asia WGS AF: 0.838 AC: 2915 AN: 3478

EpiCase AF: 0.845

EpiControl AF: 0.842

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Neuropathy, hereditary sensory and autonomic, type 2A (2)
-	-	1	Pseudohypoaldosteronism type 2C (1)
-	-	1	Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.8
DANN	Benign	0.12
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	7.2e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.069
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.053
Sift	Benign	1.0	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.15
ClinPred		0.0012	T
GERP RS		0.64
PromoterAI		-0.0064	Neutral
Varity_R		0.045
gMVP		0.067
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs956868; hg19: chr12-990912; COSMIC: COSV60040836; COSMIC: COSV60040836;