12-753238-C-G

Variant names:

• chr12-753238-C-G
• rs189463195
• NM_213655.5:c.-328C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018979.4(WNK1):​c.-328C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00898 in 316,272 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0097 (14 hom.)
• Consequence: WNK1 NM_018979.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.312
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-753238-C-G is Benign according to our data. Variant chr12-753238-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 310522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00815 (1239/152104) while in subpopulation NFE AF = 0.0133 (901/67936). AF 95% confidence interval is 0.0125. There are 6 homozygotes in GnomAd4. There are 602 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.-328C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.-328C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	ENST00000315939.11	NP_061852.3
WNK1	NM_213655.5	c.-328C>G		5_prime_UTR_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.-328C>G		5_prime_UTR_variant	Exon 1 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.-328C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.-328C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6
WNK1	ENST00000340908.9	c.-328C>G		5_prime_UTR_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.-328C>G		5_prime_UTR_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 1240 AN: 151996 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00671

GnomAD4 exome AF: 0.00975 AC: 1600 AN: 164168 Hom.: 14 Cov.: 0 AF XY: 0.00895 AC XY: 772 AN XY: 86252

African (AFR) AF: 0.000824 AC: 3 AN: 3642

American (AMR) AF: 0.00184 AC: 6 AN: 3266

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 27 AN: 5466

East Asian (EAS) AF: 0.00 AC: 0 AN: 8696

South Asian (SAS) AF: 0.00191 AC: 33 AN: 17284

European-Finnish (FIN) AF: 0.0180 AC: 207 AN: 11524

Middle Eastern (MID) AF: 0.00234 AC: 2 AN: 856

European-Non Finnish (NFE) AF: 0.0120 AC: 1238 AN: 103202

Other (OTH) AF: 0.00821 AC: 84 AN: 10232

GnomAD4 genome AF: 0.00815 AC: 1239 AN: 152104 Hom.: 6 Cov.: 31 AF XY: 0.00809 AC XY: 602 AN XY: 74376

African (AFR) AF: 0.00188 AC: 78 AN: 41538

American (AMR) AF: 0.00262 AC: 40 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0133 AC: 901 AN: 67936

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00730 Hom.: 1

Bravo AF: 0.00626

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudohypoaldosteronism type 2C Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		-0.31
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=298/2	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: rs189463195; hg19: chr12-862404;