12-908031-C-T

Variant names:

• chr12-908031-C-T
• rs4766334
• NM_213655.5:c.7584C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018979.4(WNK1):​c.6828C>T​(p.Tyr2276Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,094 control chromosomes in the GnomAD database, including 803,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74531 hom., cov: 31)
  • Exomes 𝑓: 1.0 (729078 hom.)
• Consequence: WNK1 NM_018979.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.732
• Publications: 21 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-908031-C-T is Benign according to our data. Variant chr12-908031-C-T is described in ClinVar as Benign. ClinVar VariationId is 261074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.732 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018979.4. 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.7584C>T	p.Tyr2528Tyr	synonymous	Exon 27 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.6828C>T	p.Tyr2276Tyr	synonymous	Exon 27 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.7608C>T	p.Tyr2536Tyr	synonymous	Exon 27 of 28	NP_001171914.1	Q9H4A3-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.7584C>T	p.Tyr2528Tyr	synonymous	Exon 27 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.6828C>T	p.Tyr2276Tyr	synonymous	Exon 27 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.8181C>T	p.Tyr2727Tyr	synonymous	Exon 30 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.989 AC: 150555 AN: 152206 Hom.: 74481 Cov.: 31

Gnomad AFR AF: 0.962

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.993

GnomAD2 exomes AF: 0.997 AC: 247723 AN: 248478 AF XY: 0.998

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1459929 AN: 1461770 Hom.: 729078 Cov.: 54 AF XY: 0.999 AC XY: 726378 AN XY: 727184

African (AFR) AF: 0.960 AC: 32129 AN: 33478

American (AMR) AF: 0.997 AC: 44580 AN: 44722

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26135 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39698

South Asian (SAS) AF: 1.00 AC: 86245 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53310 AN: 53310

Middle Eastern (MID) AF: 0.997 AC: 5753 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111838 AN: 1112006

Other (OTH) AF: 0.997 AC: 60241 AN: 60394

GnomAD4 genome AF: 0.989 AC: 150664 AN: 152324 Hom.: 74531 Cov.: 31 AF XY: 0.990 AC XY: 73719 AN XY: 74496

African (AFR) AF: 0.962 AC: 39991 AN: 41560

American (AMR) AF: 0.996 AC: 15237 AN: 15300

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 1.00 AC: 4822 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68032 AN: 68044

Other (OTH) AF: 0.993 AC: 2100 AN: 2114

Alfa AF: 0.995 Hom.: 101785

Bravo AF: 0.987

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Neuropathy, hereditary sensory and autonomic, type 2A (2)
-	-	2	not provided (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
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.45
DANN	Benign	0.77
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4766334; hg19: chr12-1017197; COSMIC: COSV57273756; COSMIC: COSV57273756;