NM_213655.5:c.-122C>T

Variant names:

• chr12-753444-C-T
• rs538911254
• NM_213655.5:c.-122C>T

Variant summary

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

The NM_213655.5(WNK1):​c.-122C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,339,280 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (14 hom.)
• Consequence: WNK1 NM_213655.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.345
• 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=-0.64).
• BP6: Variant 12-753444-C-T is Benign according to our data. Variant chr12-753444-C-T is described in ClinVar as [Benign]. Clinvar id is 310532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000992 (151/152264) while in subpopulation SAS AF = 0.00725 (35/4828). AF 95% confidence interval is 0.00536. There are 2 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.-122C>T		5_prime_UTR_variant	Exon 1 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.-122C>T		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.-122C>T		5_prime_UTR_variant	Exon 1 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.-122C>T		5_prime_UTR_variant	Exon 1 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152156 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00146 AC: 1730 AN: 1187016 Hom.: 14 Cov.: 17 AF XY: 0.00177 AC XY: 1043 AN XY: 589262

African (AFR) AF: 0.000110 AC: 3 AN: 27332

American (AMR) AF: 0.00146 AC: 48 AN: 32822

Ashkenazi Jewish (ASJ) AF: 0.00904 AC: 202 AN: 22354

East Asian (EAS) AF: 0.00 AC: 0 AN: 34352

South Asian (SAS) AF: 0.00904 AC: 653 AN: 72262

European-Finnish (FIN) AF: 0.0000531 AC: 2 AN: 37688

Middle Eastern (MID) AF: 0.00572 AC: 21 AN: 3670

European-Non Finnish (NFE) AF: 0.000789 AC: 715 AN: 906060

Other (OTH) AF: 0.00170 AC: 86 AN: 50476

GnomAD4 genome AF: 0.000992 AC: 151 AN: 152264 Hom.: 2 Cov.: 31 AF XY: 0.00105 AC XY: 78 AN XY: 74458

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000900 Hom.: 0

Bravo AF: 0.000812

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.97
PhyloP100		0.34
PromoterAI		-0.0098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs538911254; hg19: chr12-862610;