chrX-54249601-C-T

Variant names:

• chrX-54249601-C-T
• rs2068108655
• ENST00000354646.6:c.2747G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020922.5(WNK3):​c.2747G>A​(p.Arg916Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,096,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/22 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: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: WNK3 NM_020922.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04

Genes affected

WNK3 (HGNC:14543): (WNK lysine deficient protein kinase 3) This gene encodes a protein belonging to the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase-3-dependent pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027620941).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.2747G>A	p.Arg916Gln	missense_variant	Exon 17 of 24		NP_065973.2
WNK3	NM_001002838.4	c.2747G>A	p.Arg916Gln	missense_variant	Exon 17 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.2747G>A	p.Arg916Gln	missense_variant	Exon 17 of 23		NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.6	c.2747G>A	p.Arg916Gln	missense_variant	Exon 17 of 24	1		ENSP00000346667.2
WNK3	ENST00000375159.6	c.2747G>A	p.Arg916Gln	missense_variant	Exon 16 of 23	1
WNK3	ENST00000375169.7	c.2747G>A	p.Arg916Gln	missense_variant	Exon 17 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1096714 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362160

African (AFR) AF: 0.0000379 AC: 1 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35111

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19313

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53869

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841324

Other (OTH) AF: 0.00 AC: 0 AN: 46039

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	4.3
DANN	Benign	0.26
DEOGEN2	Benign	0.048	.;T;T;.
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.70	T;T;.;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.028	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.0	N;N;N;.
PrimateAI	Benign	0.17	T
PROVEAN	Benign	1.4	N;N;N;.
REVEL	Benign	0.039
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.023
MutPred		0.12		Loss of phosphorylation at S915 (P = 0.0912);Loss of phosphorylation at S915 (P = 0.0912);Loss of phosphorylation at S915 (P = 0.0912);Loss of phosphorylation at S915 (P = 0.0912);
MVP		0.043
MPC		0.24
ClinPred		0.068	T
GERP RS		2.6
Varity_R		0.033
gMVP		0.081
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2068108655; hg19: chrX-54276034; COSMIC: COSV63612340;