12-890496-C-T

Position:

• chr12-890496-C-T

Variant summary

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

The NM_018979.4(WNK1):​c.5492C>T​(p.Thr1831Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: WNK1 NM_018979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06

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=0.08151016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNK1	NM_213655.5	c.6248C>T	p.Thr2083Ile	missense_variant	22/28	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.5492C>T	p.Thr1831Ile	missense_variant	22/28	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.6248C>T	p.Thr2083Ile	missense_variant	22/28	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.5492C>T	p.Thr1831Ile	missense_variant	22/28	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251452 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T;T;D;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N;.;N;.;N
REVEL	Benign	0.024
Sift	Uncertain	0.0040	D;.;D;.;D
Sift4G	Benign	0.10	T;.;T;T;T
Polyphen		0.037	B;.;B;.;.
Vest4		0.27
MVP		0.043
MPC		0.20
ClinPred		0.27	T
GERP RS		3.0
Varity_R		0.089
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs373765496; hg19: chr12-999662;