rs7300444

Variant names:

• chr12-884764-C-T
• rs7300444
• NM_213655.5:c.4716C>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.3960C>T​(p.Asn1320Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,613,866 control chromosomes in the GnomAD database, including 151,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12482 hom., cov: 32)
  • Exomes 𝑓: 0.43 (139456 hom.)
• Consequence: WNK1 NM_018979.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0590
• Publications: 34 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=-0.81).
• BP6: Variant 12-884764-C-T is Benign according to our data. Variant chr12-884764-C-T is described in ClinVar as Benign. ClinVar VariationId is 137925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.059 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.513 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.4716C>T	p.Asn1572Asn	synonymous	Exon 19 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.3960C>T	p.Asn1320Asn	synonymous	Exon 19 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.4740C>T	p.Asn1580Asn	synonymous	Exon 19 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.4716C>T	p.Asn1572Asn	synonymous	Exon 19 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.3960C>T	p.Asn1320Asn	synonymous	Exon 19 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.5199C>T	p.Asn1733Asn	synonymous	Exon 20 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60638 AN: 151882 Hom.: 12474 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.421 AC: 105887 AN: 251434 AF XY: 0.420

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.434 AC: 635010 AN: 1461866 Hom.: 139456 Cov.: 69 AF XY: 0.432 AC XY: 313991 AN XY: 727236

African (AFR) AF: 0.298 AC: 9978 AN: 33478

American (AMR) AF: 0.421 AC: 18841 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 10219 AN: 26136

East Asian (EAS) AF: 0.514 AC: 20409 AN: 39700

South Asian (SAS) AF: 0.348 AC: 30034 AN: 86256

European-Finnish (FIN) AF: 0.440 AC: 23513 AN: 53420

Middle Eastern (MID) AF: 0.255 AC: 1469 AN: 5768

European-Non Finnish (NFE) AF: 0.445 AC: 495204 AN: 1111990

Other (OTH) AF: 0.420 AC: 25343 AN: 60394

GnomAD4 genome AF: 0.399 AC: 60672 AN: 152000 Hom.: 12482 Cov.: 32 AF XY: 0.400 AC XY: 29708 AN XY: 74272

African (AFR) AF: 0.305 AC: 12653 AN: 41466

American (AMR) AF: 0.417 AC: 6363 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1342 AN: 3468

East Asian (EAS) AF: 0.530 AC: 2741 AN: 5176

South Asian (SAS) AF: 0.346 AC: 1666 AN: 4820

European-Finnish (FIN) AF: 0.436 AC: 4601 AN: 10548

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29969 AN: 67942

Other (OTH) AF: 0.383 AC: 806 AN: 2106

Alfa AF: 0.420 Hom.: 46562

Bravo AF: 0.396

Asia WGS AF: 0.410 AC: 1425 AN: 3478

EpiCase AF: 0.421

EpiControl AF: 0.419

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	not provided (1)
-	-	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	-0.81
CADD	Benign	1.3
DANN	Benign	0.62
PhyloP100		-0.059
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs7300444; hg19: chr12-993930; COSMIC: COSV60031123; COSMIC: COSV60031123;