17-42795302-C-T

Variant names:

• chr17-42795302-C-T
• rs2290041
• NM_032387.5:c.2881C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032387.5(WNK4):​c.2881C>T​(p.Pro961Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,613,788 control chromosomes in the GnomAD database, including 2,880 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (1216 hom., cov: 31)
  • Exomes 𝑓: 0.016 (1664 hom.)
• Consequence: WNK4 NM_032387.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.45
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034779012).
• BP6: Variant 17-42795302-C-T is Benign according to our data. Variant chr17-42795302-C-T is described in ClinVar as Benign. ClinVar VariationId is 323347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

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.2881C>T	p.Pro961Ser	missense	Exon 14 of 19	NP_115763.2
	WNK4	NM_001321299.2		c.1873C>T	p.Pro625Ser	missense	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.2881C>T	p.Pro961Ser	missense	Exon 14 of 19	ENSP00000246914.4	Q96J92-1
	WNK4	ENST00000591448.5	TSL:1	n.*1382C>T		non_coding_transcript_exon	Exon 13 of 18	ENSP00000467088.1	K7ENT7
	WNK4	ENST00000591448.5	TSL:1	n.*1382C>T		3_prime_UTR	Exon 13 of 18	ENSP00000467088.1	K7ENT7

Frequencies

GnomAD3 genomes AF: 0.0731 AC: 11102 AN: 151858 Hom.: 1202 Cov.: 31

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0432

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0360 AC: 9012 AN: 250252 AF XY: 0.0351

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.0447

Gnomad FIN exome AF: 0.00490

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0156 AC: 22754 AN: 1461812 Hom.: 1664 Cov.: 36 AF XY: 0.0174 AC XY: 12638 AN XY: 727216

African (AFR) AF: 0.235 AC: 7875 AN: 33480

American (AMR) AF: 0.0179 AC: 801 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 271 AN: 26122

East Asian (EAS) AF: 0.0391 AC: 1554 AN: 39698

South Asian (SAS) AF: 0.100 AC: 8630 AN: 86258

European-Finnish (FIN) AF: 0.00523 AC: 279 AN: 53396

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5768

European-Non Finnish (NFE) AF: 0.00129 AC: 1434 AN: 1111978

Other (OTH) AF: 0.0298 AC: 1801 AN: 60394

GnomAD4 genome AF: 0.0734 AC: 11160 AN: 151976 Hom.: 1216 Cov.: 31 AF XY: 0.0731 AC XY: 5432 AN XY: 74328

African (AFR) AF: 0.233 AC: 9651 AN: 41362

American (AMR) AF: 0.0295 AC: 451 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.0435 AC: 224 AN: 5154

South Asian (SAS) AF: 0.104 AC: 500 AN: 4820

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00197 AC: 134 AN: 67956

Other (OTH) AF: 0.0545 AC: 115 AN: 2110

Alfa AF: 0.0299 Hom.: 790

Bravo AF: 0.0798

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.228 AC: 1003

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0407 AC: 4944

Asia WGS AF: 0.0820 AC: 285 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Pseudohypoaldosteronism type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.63
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.084
Sift	Benign	0.19	T
Sift4G	Benign	0.20	T
Polyphen		0.51	P
Vest4		0.059
MPC		0.17
ClinPred		0.014	T
GERP RS		4.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.8
Varity_R		0.056
gMVP		0.23
Mutation Taster		=89/11	polymorphism (auto)

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: rs2290041; hg19: chr17-40947320; COSMIC: COSV55902632; COSMIC: COSV55902632;