17-42796244-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032387.5(WNK4):​c.3553C>A​(p.Arg1185Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WNK4 NM_032387.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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>A	p.Arg1185Ser	missense	Exon 17 of 19	NP_115763.2
	WNK4	NM_001321299.2		c.2545C>A	p.Arg849Ser	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>A	p.Arg1185Ser	missense	Exon 17 of 19	ENSP00000246914.4	Q96J92-1
	WNK4	ENST00000591448.5	TSL:1	n.*2054C>A		non_coding_transcript_exon	Exon 16 of 18	ENSP00000467088.1	K7ENT7
	WNK4	ENST00000591448.5	TSL:1	n.*2054C>A		3_prime_UTR	Exon 16 of 18	ENSP00000467088.1	K7ENT7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459076 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725822

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111164

Other (OTH) AF: 0.00 AC: 0 AN: 60164

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.47		Gain of phosphorylation at R1185 (P = 0.0081)
MVP		0.91
MPC		0.74
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.38
gMVP		0.68

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: rs137853095; hg19: chr17-40948262;