rs72647374

Variant names:

• chr12-754249-C-T
• rs72647374
• NM_213655.5:c.684C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018979.4(WNK1):​c.684C>T​(p.Gly228Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,712 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (11 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (12 hom.)
• Consequence: WNK1 NM_018979.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.58
• Publications: 0 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=-0.5).
• BP6: Variant 12-754249-C-T is Benign according to our data. Variant chr12-754249-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00692 (1055/152364) while in subpopulation AFR AF = 0.0222 (922/41584). AF 95% confidence interval is 0.021. There are 11 homozygotes in GnomAd4. There are 517 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

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.684C>T	p.Gly228Gly	synonymous	Exon 1 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.684C>T	p.Gly228Gly	synonymous	Exon 1 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.684C>T	p.Gly228Gly	synonymous	Exon 1 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.684C>T	p.Gly228Gly	synonymous	Exon 1 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.684C>T	p.Gly228Gly	synonymous	Exon 1 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.684C>T	p.Gly228Gly	synonymous	Exon 1 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1055 AN: 152246 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00279 AC: 700 AN: 251052 AF XY: 0.00226

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000723

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00125 AC: 1824 AN: 1461348 Hom.: 12 Cov.: 93 AF XY: 0.00113 AC XY: 825 AN XY: 726980

African (AFR) AF: 0.0234 AC: 782 AN: 33480

American (AMR) AF: 0.00329 AC: 147 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 315 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52894

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000352 AC: 391 AN: 1112002

Other (OTH) AF: 0.00268 AC: 162 AN: 60388

GnomAD4 genome AF: 0.00692 AC: 1055 AN: 152364 Hom.: 11 Cov.: 34 AF XY: 0.00694 AC XY: 517 AN XY: 74516

African (AFR) AF: 0.0222 AC: 922 AN: 41584

American (AMR) AF: 0.00379 AC: 58 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68038

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00555 Hom.: 9

Bravo AF: 0.00803

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

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: rs72647374; hg19: chr12-863415;