12-753475-T-G

Variant names:

• chr12-753475-T-G
• rs3088353
• NM_213655.5:c.-91T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018979.4(WNK1):​c.-91T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,561,778 control chromosomes in the GnomAD database, including 157,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13399 hom., cov: 32)
  • Exomes 𝑓: 0.45 (144218 hom.)
• Consequence: WNK1 NM_018979.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.835
• Publications: 11 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=-0.92).
• BP6: Variant 12-753475-T-G is Benign according to our data. Variant chr12-753475-T-G is described in ClinVar as [Benign]. Clinvar id is 310533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.-91T>G		5_prime_UTR_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.-91T>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.-91T>G		5_prime_UTR_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.-91T>G		5_prime_UTR_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62068 AN: 151902 Hom.: 13391 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.411

GnomAD4 exome AF: 0.448 AC: 631840 AN: 1409762 Hom.: 144218 Cov.: 27 AF XY: 0.446 AC XY: 311153 AN XY: 698012

African (AFR) AF: 0.271 AC: 8670 AN: 32030

American (AMR) AF: 0.481 AC: 19806 AN: 41188

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 10384 AN: 25502

East Asian (EAS) AF: 0.321 AC: 11981 AN: 37372

South Asian (SAS) AF: 0.349 AC: 28774 AN: 82538

European-Finnish (FIN) AF: 0.558 AC: 26562 AN: 47586

Middle Eastern (MID) AF: 0.389 AC: 1582 AN: 4072

European-Non Finnish (NFE) AF: 0.462 AC: 499115 AN: 1081360

Other (OTH) AF: 0.430 AC: 24966 AN: 58114

GnomAD4 genome AF: 0.409 AC: 62100 AN: 152016 Hom.: 13399 Cov.: 32 AF XY: 0.413 AC XY: 30677 AN XY: 74330

African (AFR) AF: 0.277 AC: 11501 AN: 41484

American (AMR) AF: 0.453 AC: 6921 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1411 AN: 3470

East Asian (EAS) AF: 0.319 AC: 1643 AN: 5146

South Asian (SAS) AF: 0.327 AC: 1574 AN: 4818

European-Finnish (FIN) AF: 0.568 AC: 6012 AN: 10576

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.465 AC: 31589 AN: 67932

Other (OTH) AF: 0.407 AC: 857 AN: 2106

Alfa AF: 0.311 Hom.: 870

Bravo AF: 0.397

Asia WGS AF: 0.290 AC: 1009 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Pseudohypoaldosteronism type 2C Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.6
DANN	Benign	0.73
PhyloP100		-0.83
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=298/2	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: rs3088353; hg19: chr12-862641; COSMIC: COSV60037615;