rs148639270

Variant names:

• chr12-889172-A-C
• rs148639270
• NM_213655.5:c.6153A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-889172-A-C
• chr12-889172-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_213655.5(WNK1):​c.6153A>C​(p.Gln2051His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 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. Synonymous variant affecting the same amino acid position (i.e. Q2051Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WNK1 NM_213655.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24564433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.6153A>C	p.Gln2051His	missense_variant	Exon 21 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.5397A>C	p.Gln1799His	missense_variant	Exon 21 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.6153A>C	p.Gln2051His	missense_variant	Exon 21 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.5397A>C	p.Gln1799His	missense_variant	Exon 21 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111966

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.5	.;.;M;.;.
PhyloP100		0.37
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D;.;D;.;D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Benign	0.077	T;.;T;T;T
Polyphen		1.0	D;.;D;.;.
Vest4		0.44
MutPred		0.16		.;.;Loss of helix (P = 0.0558);.;.;
MVP		0.38
MPC		0.53
ClinPred		0.99	D
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.46
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148639270; hg19: chr12-998338;