12-753541-C-G

Variant names:

• chr12-753541-C-G
• rs72647367
• NM_213655.5:c.-25C>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.-25C>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 0.00906 in 1,611,392 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (75 hom.)
• Consequence: WNK1 NM_018979.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.616
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-753541-C-G is Benign according to our data. Variant chr12-753541-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310535.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 = 0.0067 (1020/152314) while in subpopulation NFE AF = 0.00992 (675/68026). AF 95% confidence interval is 0.0093. There are 6 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.-25C>G		5_prime_UTR	Exon 1 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.-25C>G		5_prime_UTR	Exon 1 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.-25C>G		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.-25C>G		5_prime_UTR	Exon 1 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.-25C>G		5_prime_UTR	Exon 1 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.-25C>G		5_prime_UTR	Exon 1 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.00670 AC: 1020 AN: 152196 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00753 AC: 1799 AN: 238868 AF XY: 0.00752

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.000615

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00630

GnomAD4 exome AF: 0.00931 AC: 13578 AN: 1459078 Hom.: 75 Cov.: 32 AF XY: 0.00898 AC XY: 6518 AN XY: 725782

African (AFR) AF: 0.00141 AC: 47 AN: 33434

American (AMR) AF: 0.00262 AC: 117 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00118 AC: 102 AN: 86194

European-Finnish (FIN) AF: 0.0178 AC: 926 AN: 51882

Middle Eastern (MID) AF: 0.000592 AC: 3 AN: 5064

European-Non Finnish (NFE) AF: 0.0107 AC: 11890 AN: 1111740

Other (OTH) AF: 0.00783 AC: 472 AN: 60266

GnomAD4 genome AF: 0.00670 AC: 1020 AN: 152314 Hom.: 6 Cov.: 33 AF XY: 0.00669 AC XY: 498 AN XY: 74466

African (AFR) AF: 0.00156 AC: 65 AN: 41578

American (AMR) AF: 0.00274 AC: 42 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0187 AC: 198 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00992 AC: 675 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00556

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Pseudohypoaldosteronism type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	16
DANN	Benign	0.61
PhyloP100		0.62
PromoterAI		-0.0012	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: rs72647367; hg19: chr12-862707;