12-753332-T-C

Variant names:

• chr12-753332-T-C
• rs368645018
• NM_213655.5:c.-234T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_018979.4(WNK1):​c.-234T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000755 in 582,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: WNK1 NM_018979.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.203
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000125 (19/151988) while in subpopulation EAS AF = 0.0035 (18/5150). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-234T>C		5_prime_UTR	Exon 1 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.-234T>C		5_prime_UTR	Exon 1 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.-234T>C		5_prime_UTR	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.-234T>C		5_prime_UTR	Exon 1 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.-234T>C		5_prime_UTR	Exon 1 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.-234T>C		5_prime_UTR	Exon 1 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.0000581 AC: 25 AN: 430490 Hom.: 0 Cov.: 5 AF XY: 0.0000528 AC XY: 12 AN XY: 227104

African (AFR) AF: 0.00 AC: 0 AN: 9646

American (AMR) AF: 0.00 AC: 0 AN: 16162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12440

East Asian (EAS) AF: 0.000720 AC: 20 AN: 27784

South Asian (SAS) AF: 0.00 AC: 0 AN: 43486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1868

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 265654

Other (OTH) AF: 0.000202 AC: 5 AN: 24726

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151988 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00350 AC: 18 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67944

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.00348 AC: 12 AN: 3466

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pseudohypoaldosteronism type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.71
PhyloP100		0.20
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs368645018; hg19: chr12-862498;