rs267603708

Variant names:

• chr12-883564-C-A
• rs267603708
• NM_213655.5:c.4415C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-883564-C-A
• chr12-883564-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018979.4(WNK1):​c.3659C>A​(p.Ser1220Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1220F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27810353).

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.4415C>A	p.Ser1472Tyr	missense	Exon 16 of 28	NP_998820.3
	WNK1	NM_018979.4	MANE Select	c.3659C>A	p.Ser1220Tyr	missense	Exon 16 of 28	NP_061852.3
	WNK1	NM_001184985.2		c.4439C>A	p.Ser1480Tyr	missense	Exon 16 of 28	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.4415C>A	p.Ser1472Tyr	missense	Exon 16 of 28	ENSP00000341292.5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.3659C>A	p.Ser1220Tyr	missense	Exon 16 of 28	ENSP00000313059.6
	WNK1	ENST00000530271.6	TSL:1	c.4898C>A	p.Ser1633Tyr	missense	Exon 17 of 31	ENSP00000433548.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.16
Sift	Benign	0.16	T
Sift4G	Benign	1.0	T
Polyphen		0.98	D
Vest4		0.40
MutPred		0.20		Loss of methylation at K1222 (P = 0.0788)
MVP		0.082
MPC		0.30
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.44
Mutation Taster		=70/30	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: rs267603708; hg19: chr12-992730;