17-42796244-C-G

Variant names:

• chr17-42796244-C-G
• rs137853095
• NM_032387.5:c.3553C>G

Variant summary

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

The NM_032387.5(WNK4):​c.3553C>G​(p.Arg1185Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1185C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WNK4 NM_032387.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60
• Publications: 18 publications found

Genes affected

WNK4 (HGNC:14544): (WNK lysine deficient protein kinase 4) This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

COA3 (HGNC:24990): (cytochrome c oxidase assembly factor 3) This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function. [provided by RefSeq, Nov 2012]

COA3 Gene-Disease associations (from GenCC):

• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• mitochondrial complex IV deficiency, nuclear type 14

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032387.5. 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
	WNK4	NM_032387.5	MANE Select	c.3553C>G	p.Arg1185Gly	missense	Exon 17 of 19	NP_115763.2
	WNK4	NM_001321299.2		c.2545C>G	p.Arg849Gly	missense	Exon 16 of 18	NP_001308228.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK4	ENST00000246914.10	TSL:1 MANE Select	c.3553C>G	p.Arg1185Gly	missense	Exon 17 of 19	ENSP00000246914.4	Q96J92-1
	WNK4	ENST00000591448.5	TSL:1	n.*2054C>G		non_coding_transcript_exon	Exon 16 of 18	ENSP00000467088.1	K7ENT7
	WNK4	ENST00000591448.5	TSL:1	n.*2054C>G		3_prime_UTR	Exon 16 of 18	ENSP00000467088.1	K7ENT7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.017	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.44		Loss of MoRF binding (P = 0.0488)
MVP		0.93
MPC		0.79
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.31
gMVP		0.63

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: rs137853095; hg19: chr17-40948262;