rs1012729

Variant names:

• chr12-878316-G-A
• rs1012729
• NM_213655.5:c.3822G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-878316-G-A
• chr12-878316-G-C
• chr12-878316-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_018979.4(WNK1):​c.2328G>A​(p.Gln776Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,613,584 control chromosomes in the GnomAD database, including 441,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37571 hom., cov: 30)
  • Exomes 𝑓: 0.74 (403847 hom.)
• Consequence: WNK1 NM_018979.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.842
• Publications: 32 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.121).
• BP6: Variant 12-878316-G-A is Benign according to our data. Variant chr12-878316-G-A is described in ClinVar as Benign. ClinVar VariationId is 261067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.842 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 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.3822G>A	p.Gln1274Gln	synonymous	Exon 12 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.2328G>A	p.Gln776Gln	synonymous	Exon 10 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.3567G>A	p.Gln1189Gln	synonymous	Exon 11 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.3822G>A	p.Gln1274Gln	synonymous	Exon 12 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.2328G>A	p.Gln776Gln	synonymous	Exon 10 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.3567G>A	p.Gln1189Gln	synonymous	Exon 11 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.698 AC: 105889 AN: 151722 Hom.: 37549 Cov.: 30

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.678

Gnomad FIN AF: 0.812

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.686

GnomAD2 exomes AF: 0.739 AC: 185645 AN: 251352 AF XY: 0.738

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.764

Gnomad ASJ exome AF: 0.688

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.804

Gnomad NFE exome AF: 0.753

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.742 AC: 1084659 AN: 1461748 Hom.: 403847 Cov.: 62 AF XY: 0.741 AC XY: 538598 AN XY: 727178

African (AFR) AF: 0.560 AC: 18742 AN: 33472

American (AMR) AF: 0.763 AC: 34127 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 17787 AN: 26130

East Asian (EAS) AF: 0.789 AC: 31313 AN: 39692

South Asian (SAS) AF: 0.696 AC: 60048 AN: 86254

European-Finnish (FIN) AF: 0.804 AC: 42973 AN: 53418

Middle Eastern (MID) AF: 0.637 AC: 3676 AN: 5768

European-Non Finnish (NFE) AF: 0.748 AC: 831929 AN: 1111900

Other (OTH) AF: 0.730 AC: 44064 AN: 60392

GnomAD4 genome AF: 0.698 AC: 105960 AN: 151836 Hom.: 37571 Cov.: 30 AF XY: 0.701 AC XY: 51999 AN XY: 74192

African (AFR) AF: 0.565 AC: 23353 AN: 41322

American (AMR) AF: 0.741 AC: 11321 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2333 AN: 3466

East Asian (EAS) AF: 0.808 AC: 4182 AN: 5176

South Asian (SAS) AF: 0.679 AC: 3266 AN: 4810

European-Finnish (FIN) AF: 0.812 AC: 8547 AN: 10524

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50547 AN: 67958

Other (OTH) AF: 0.681 AC: 1435 AN: 2106

Alfa AF: 0.720 Hom.: 57675

Bravo AF: 0.689

Asia WGS AF: 0.703 AC: 2444 AN: 3478

EpiCase AF: 0.722

EpiControl AF: 0.730

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	-0.80
CADD	Benign	0.53
DANN	Benign	0.33
PhyloP100		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs1012729; hg19: chr12-987482; COSMIC: COSV60028268; COSMIC: COSV60028268;