NM_213655.5:c.4245+4C>T

Variant names:

• chr12-883063-C-T
• rs34032084
• NM_213655.5:c.4245+4C>T

Variant summary

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

The NM_213655.5(WNK1):​c.4245+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,583,204 control chromosomes in the GnomAD database, including 14,580 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (938 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13642 hom.)
• Consequence: WNK1 NM_213655.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001857
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.228
• Publications: 9 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=-0.52).
• BP6: Variant 12-883063-C-T is Benign according to our data. Variant chr12-883063-C-T is described in ClinVar as Benign. ClinVar VariationId is 261071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213655.5. 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.4245+4C>T		splice_region intron	N/A	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.3489+4C>T		splice_region intron	N/A	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.4269+4C>T		splice_region intron	N/A	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.4245+4C>T		splice_region intron	N/A	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.3489+4C>T		splice_region intron	N/A	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.4728+4C>T		splice_region intron	N/A	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15600 AN: 152070 Hom.: 939 Cov.: 33

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0971

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.116 AC: 29237 AN: 251360 AF XY: 0.123

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0835

Gnomad FIN exome AF: 0.0914

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.135 AC: 192763 AN: 1431016 Hom.: 13642 Cov.: 26 AF XY: 0.136 AC XY: 97430 AN XY: 714218

African (AFR) AF: 0.0441 AC: 1447 AN: 32790

American (AMR) AF: 0.0612 AC: 2735 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2984 AN: 25922

East Asian (EAS) AF: 0.113 AC: 4460 AN: 39488

South Asian (SAS) AF: 0.173 AC: 14843 AN: 85656

European-Finnish (FIN) AF: 0.0974 AC: 5204 AN: 53404

Middle Eastern (MID) AF: 0.152 AC: 868 AN: 5728

European-Non Finnish (NFE) AF: 0.141 AC: 152671 AN: 1083968

Other (OTH) AF: 0.127 AC: 7551 AN: 59382

GnomAD4 genome AF: 0.102 AC: 15599 AN: 152188 Hom.: 938 Cov.: 33 AF XY: 0.101 AC XY: 7527 AN XY: 74404

African (AFR) AF: 0.0444 AC: 1844 AN: 41548

American (AMR) AF: 0.0880 AC: 1345 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3472

East Asian (EAS) AF: 0.0940 AC: 487 AN: 5182

South Asian (SAS) AF: 0.168 AC: 809 AN: 4818

European-Finnish (FIN) AF: 0.0971 AC: 1028 AN: 10582

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9295 AN: 67984

Other (OTH) AF: 0.114 AC: 242 AN: 2114

Alfa AF: 0.120 Hom.: 694

Bravo AF: 0.0982

Asia WGS AF: 0.125 AC: 435 AN: 3476

EpiCase AF: 0.138

EpiControl AF: 0.143

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Pseudohypoaldosteronism type 2C (1)
-	-	1	Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.016
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: rs34032084; hg19: chr12-992229; COSMIC: COSV60025777; COSMIC: COSV60025777;