rs72650768

Variant names:

• chr12-900651-C-A
• rs72650768
• NM_213655.5:c.7380C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-900651-C-A
• chr12-900651-C-G
• chr12-900651-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_018979.4(WNK1):​c.6624C>A​(p.Ser2208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2208S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.45
• Publications: 1 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), G2P, Ambry Genetics, ClinGen
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0143708885).
• BP6: Variant 12-900651-C-A is Benign according to our data. Variant chr12-900651-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195979.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00112 (170/152298) while in subpopulation AFR AF = 0.0039 (162/41564). AF 95% confidence interval is 0.00341. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.7380C>A	p.Ser2460Arg	missense	Exon 26 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.6624C>A	p.Ser2208Arg	missense	Exon 26 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.7404C>A	p.Ser2468Arg	missense	Exon 26 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.7380C>A	p.Ser2460Arg	missense	Exon 26 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.6624C>A	p.Ser2208Arg	missense	Exon 26 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.7863C>A	p.Ser2621Arg	missense	Exon 27 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000306 AC: 77 AN: 251416 AF XY: 0.000191

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000798 AC XY: 58 AN XY: 727244

African (AFR) AF: 0.00370 AC: 124 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74478

African (AFR) AF: 0.00390 AC: 162 AN: 41564

American (AMR) AF: 0.0000653 AC: 1 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.00126

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (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
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.40		Gain of solvent accessibility (P = 0.0055)
MVP		0.69
MPC		0.60
ClinPred		0.087	T
GERP RS		2.2
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.50
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72650768; hg19: chr12-1009817;