12-878316-G-T

Variant names:

• chr12-878316-G-T
• rs1012729
• NM_213655.5:c.3822G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018979.4(WNK1):​c.2328G>T​(p.Gln776His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. Q776Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.842

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11543754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.3822G>T	p.Gln1274His	missense_variant	Exon 12 of 28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.2328G>T	p.Gln776His	missense_variant	Exon 10 of 28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.3822G>T	p.Gln1274His	missense_variant	Exon 12 of 28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.2328G>T	p.Gln776His	missense_variant	Exon 10 of 28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461852 Hom.: 0 Cov.: 62 AF XY: 0.0000179 AC XY: 13 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.1
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T;.;T;.;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;.;M;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D;N;N;.;D;D
REVEL	Benign	0.19
Sift	Benign	0.069	T;D;D;.;D;D
Sift4G	Benign	0.41	T;.;T;T;T;T
Polyphen		1.0	D;.;D;.;.;.
Vest4		0.24
MutPred		0.12		.;.;Gain of glycosylation at S775 (P = 0.146);.;.;.;
MVP		0.14
MPC		0.11
ClinPred		0.42	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs1012729; hg19: chr12-987482;