chr12-879392-C-T

Variant names:

• chr12-879392-C-T
• rs880054
• NM_213655.5:c.3867+1031C>T

Variant summary

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

The NM_001184985.2(WNK1):​c.3612+1031C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 149,340 control chromosomes in the GnomAD database, including 22,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.55 (22974 hom., cov: 28)
• Consequence: WNK1 NM_001184985.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0720
• Publications: 20 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=-0.62).
• BP6: Variant 12-879392-C-T is Benign according to our data. Variant chr12-879392-C-T is described in ClinVar as Benign. ClinVar VariationId is 538531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184985.2. 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.3867+1031C>T		intron	N/A	NP_998820.3
	WNK1	NM_018979.4	MANE Select	c.2374-181C>T		intron	N/A	NP_061852.3
	WNK1	NM_001184985.2		c.3612+1031C>T		intron	N/A	NP_001171914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK1	ENST00000340908.9	TSL:5 MANE Plus Clinical	c.3867+1031C>T		intron	N/A	ENSP00000341292.5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.2374-181C>T		intron	N/A	ENSP00000313059.6
	WNK1	ENST00000530271.6	TSL:1	c.3613-181C>T		intron	N/A	ENSP00000433548.3

Frequencies

GnomAD3 genomes AF: 0.548 AC: 81743 AN: 149252 Hom.: 22969 Cov.: 28

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.532

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.548 AC: 81779 AN: 149340 Hom.: 22974 Cov.: 28 AF XY: 0.552 AC XY: 40141 AN XY: 72710

African (AFR) AF: 0.426 AC: 17270 AN: 40554

American (AMR) AF: 0.548 AC: 8218 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1875 AN: 3466

East Asian (EAS) AF: 0.711 AC: 3637 AN: 5118

South Asian (SAS) AF: 0.496 AC: 2365 AN: 4772

European-Finnish (FIN) AF: 0.703 AC: 6752 AN: 9608

Middle Eastern (MID) AF: 0.497 AC: 143 AN: 288

European-Non Finnish (NFE) AF: 0.589 AC: 39793 AN: 67570

Other (OTH) AF: 0.530 AC: 1092 AN: 2060

Alfa AF: 0.565 Hom.: 46983

Bravo AF: 0.533

Asia WGS AF: 0.558 AC: 1939 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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	-0.62
CADD	Benign	6.9
DANN	Benign	0.72
PhyloP100		-0.072
Mutation Taster		=100/0	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: rs880054; hg19: chr12-988558;