chr12-896637-T-C

Variant names:

• chr12-896637-T-C
• rs151331381
• NM_213655.5:c.6906T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_018979.4(WNK1):​c.6150T>C​(p.Leu2050Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,608,302 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L2050L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: WNK1 NM_018979.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.754
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-896637-T-C is Benign according to our data. Variant chr12-896637-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289744.
• BP7: Synonymous conserved (PhyloP=0.754 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00164 (246/150444) while in subpopulation AMR AF = 0.00293 (44/15006). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.6906T>C	p.Leu2302Leu	synonymous	Exon 24 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.6150T>C	p.Leu2050Leu	synonymous	Exon 24 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.6930T>C	p.Leu2310Leu	synonymous	Exon 24 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.6906T>C	p.Leu2302Leu	synonymous	Exon 24 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.6150T>C	p.Leu2050Leu	synonymous	Exon 24 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.7389T>C	p.Leu2463Leu	synonymous	Exon 25 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 247 AN: 150326 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.000579

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000863

Gnomad FIN AF: 0.0000962

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00342

GnomAD2 exomes AF: 0.00134 AC: 333 AN: 248420 AF XY: 0.00139

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000305

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00165 AC: 2404 AN: 1457858 Hom.: 3 Cov.: 31 AF XY: 0.00160 AC XY: 1159 AN XY: 725030

African (AFR) AF: 0.000272 AC: 9 AN: 33100

American (AMR) AF: 0.00233 AC: 102 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.000462 AC: 12 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000408 AC: 35 AN: 85874

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53354

Middle Eastern (MID) AF: 0.00332 AC: 19 AN: 5730

European-Non Finnish (NFE) AF: 0.00192 AC: 2132 AN: 1110162

Other (OTH) AF: 0.00148 AC: 89 AN: 60158

GnomAD4 genome AF: 0.00164 AC: 246 AN: 150444 Hom.: 0 Cov.: 28 AF XY: 0.00147 AC XY: 108 AN XY: 73380

African (AFR) AF: 0.000367 AC: 15 AN: 40824

American (AMR) AF: 0.00293 AC: 44 AN: 15006

Ashkenazi Jewish (ASJ) AF: 0.000579 AC: 2 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000864 AC: 4 AN: 4630

European-Finnish (FIN) AF: 0.0000962 AC: 1 AN: 10398

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 172 AN: 67706

Other (OTH) AF: 0.00338 AC: 7 AN: 2068

Alfa AF: 0.00180 Hom.: 1

Bravo AF: 0.00197

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	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	-0.49
CADD	Benign	8.1
DANN	Benign	0.81
PhyloP100		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs151331381; hg19: chr12-1005803;