NM_032387.5:c.2823G>C

Variant names:

• chr17-42795244-G-C
• rs371107660
• NM_032387.5:c.2823G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_032387.5(WNK4):​c.2823G>C​(p.Leu941Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. L941L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WNK4 NM_032387.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.355
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=0.355 with no splicing effect.

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.2823G>C	p.Leu941Leu	synonymous	Exon 14 of 19	NP_115763.2
	WNK4	NM_001321299.2		c.1815G>C	p.Leu605Leu	synonymous	Exon 13 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.2823G>C	p.Leu941Leu	synonymous	Exon 14 of 19	ENSP00000246914.4	Q96J92-1
	WNK4	ENST00000591448.5	TSL:1	n.*1324G>C		non_coding_transcript_exon	Exon 13 of 18	ENSP00000467088.1	K7ENT7
	WNK4	ENST00000591448.5	TSL:1	n.*1324G>C		3_prime_UTR	Exon 13 of 18	ENSP00000467088.1	K7ENT7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.73
PhyloP100		0.35

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: rs371107660; hg19: chr17-40947262;