12-861247-A-G

Variant names:

• chr12-861247-A-G
• rs149388376
• NM_213655.5:c.1855A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018979.4(WNK1):​c.1855A>G​(p.Thr619Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,144 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T619P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.730
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011191517).
• BP6: Variant 12-861247-A-G is Benign according to our data. Variant chr12-861247-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310741.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00086 (131/152272) while in subpopulation NFE AF = 0.00149 (101/68012). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	NP_998820.3	Q9H4A3-5
	WNK1	NM_018979.4	MANE Select	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	NP_061852.3	Q9H4A3-1
	WNK1	NM_001184985.2		c.1855A>G	p.Thr619Ala	missense	Exon 7 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.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	ENSP00000341292.5	Q9H4A3-5
	WNK1	ENST00000315939.11	TSL:1 MANE Select	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 28	ENSP00000313059.6	Q9H4A3-1
	WNK1	ENST00000530271.6	TSL:1	c.1855A>G	p.Thr619Ala	missense	Exon 7 of 31	ENSP00000433548.3	Q9H4A3-7

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.00148

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000793 AC: 199 AN: 250818 AF XY: 0.000804

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00140 AC: 2048 AN: 1461872 Hom.: 2 Cov.: 33 AF XY: 0.00134 AC XY: 973 AN XY: 727236

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.00119 AC: 53 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00172 AC: 1915 AN: 1111998

Other (OTH) AF: 0.00118 AC: 71 AN: 60392

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.000725 AC XY: 54 AN XY: 74470

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.00124 AC: 19 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 68012

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00109

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000758 AC: 92

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Pseudohypoaldosteronism type 2C (1)
-	-	1	Pseudohypoaldosteronism type 2C;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	WNK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.73
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.078
Sift	Benign	0.23	T
Sift4G	Benign	0.81	T
Polyphen		0.0090	B
Vest4		0.12
MVP		0.11
MPC		0.12
ClinPred		0.015	T
GERP RS		3.4
PromoterAI		0.012	Neutral
Varity_R		0.061
gMVP		0.17
Mutation Taster		=83/17	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: rs149388376; hg19: chr12-970413;