rs35706572

Variant names:

• chr12-865142-T-TC
• rs35706572
• NM_213655.5:c.2175dupC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_213655.5(WNK1):​c.2175dupC​(p.Ile726HisfsTer45) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,531,260 control chromosomes in the GnomAD database, including 62,024 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I726I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.26 (5511 hom., cov: 21)
  • Exomes 𝑓: 0.28 (56513 hom.)
• Consequence: WNK1 NM_213655.5 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.43
• Publications: 3 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

ENSG00000285704 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 12-865142-T-TC is Benign according to our data. Variant chr12-865142-T-TC is described in ClinVar as Benign. ClinVar VariationId is 1166421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213655.5. 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.2175dupC	p.Ile726HisfsTer45	frameshift	Exon 9 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.2139+2875dupC		intron	N/A	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.2140-2721dupC		intron	N/A	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.2175dupC	p.Ile726HisfsTer45	frameshift	Exon 9 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.2139+2875dupC		intron	N/A	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.2140-2721dupC		intron	N/A	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39874 AN: 151880 Hom.: 5509 Cov.: 21

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.248 AC: 32097 AN: 129242 AF XY: 0.254

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.282 AC: 389156 AN: 1379262 Hom.: 56513 Cov.: 34 AF XY: 0.283 AC XY: 192336 AN XY: 679836

African (AFR) AF: 0.233 AC: 7345 AN: 31488

American (AMR) AF: 0.172 AC: 6100 AN: 35438

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 10818 AN: 25006

East Asian (EAS) AF: 0.137 AC: 4886 AN: 35654

South Asian (SAS) AF: 0.247 AC: 19468 AN: 78808

European-Finnish (FIN) AF: 0.247 AC: 8357 AN: 33798

Middle Eastern (MID) AF: 0.384 AC: 2179 AN: 5678

European-Non Finnish (NFE) AF: 0.291 AC: 313481 AN: 1075674

Other (OTH) AF: 0.286 AC: 16522 AN: 57718

GnomAD4 genome AF: 0.262 AC: 39891 AN: 151998 Hom.: 5511 Cov.: 21 AF XY: 0.259 AC XY: 19214 AN XY: 74286

African (AFR) AF: 0.228 AC: 9465 AN: 41446

American (AMR) AF: 0.219 AC: 3354 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1524 AN: 3462

East Asian (EAS) AF: 0.116 AC: 600 AN: 5172

South Asian (SAS) AF: 0.238 AC: 1146 AN: 4806

European-Finnish (FIN) AF: 0.251 AC: 2646 AN: 10556

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20125 AN: 67968

Other (OTH) AF: 0.282 AC: 594 AN: 2110

Alfa AF: 0.295 Hom.: 1535

Bravo AF: 0.259

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (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
PhyloP100		7.4
Mutation Taster		=166/34	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: rs35706572; hg19: chr12-974308; COSMIC: COSV60045433; COSMIC: COSV60045433;