chrX-54198553-G-C

Variant names:

• chrX-54198553-G-C
• rs782683979
• ENST00000354646.7:c.5174C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000354646.7(WNK3):​c.5174C>G​(p.Pro1725Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000621 in 1,207,881 control chromosomes in the GnomAD database, including 1 homozygotes. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign 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. P1725L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000065 (1 hom. 28 hem.)
• Consequence: WNK3 ENST00000354646.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93
• Publications: 0 publications found

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]

WNK3 Gene-Disease associations (from GenCC):

• Prieto syndrome

  Inheritance: XL Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02577576).
• BS2: High Hemizygotes in GnomAdExome4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK3	NM_020922.5	c.5174C>G	p.Pro1725Arg	missense_variant	Exon 24 of 24		NP_065973.2
WNK3	NM_001002838.4	c.5003C>G	p.Pro1668Arg	missense_variant	Exon 23 of 23		NP_001002838.1
WNK3	NM_001395166.1	c.5003C>G	p.Pro1668Arg	missense_variant	Exon 23 of 23		NP_001382095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK3	ENST00000354646.7	c.5174C>G	p.Pro1725Arg	missense_variant	Exon 24 of 24	1		ENSP00000346667.2
WNK3	ENST00000375169.7	c.5003C>G	p.Pro1668Arg	missense_variant	Exon 23 of 23	5		ENSP00000364312.3

Frequencies

GnomAD3 genomes AF: 0.0000363 AC: 4 AN: 110232 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00160

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 20 AN: 182699 AF XY: 0.000104

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000647 AC: 71 AN: 1097600 Hom.: 1 Cov.: 30 AF XY: 0.0000771 AC XY: 28 AN XY: 362966

African (AFR) AF: 0.0000379 AC: 1 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35185

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00120 AC: 65 AN: 53963

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841764

Other (OTH) AF: 0.000109 AC: 5 AN: 46073

GnomAD4 genome AF: 0.0000363 AC: 4 AN: 110281 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32565

African (AFR) AF: 0.00 AC: 0 AN: 30353

American (AMR) AF: 0.00 AC: 0 AN: 10216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2627

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.00160 AC: 4 AN: 2496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5859

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52817

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000824 AC: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.026	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.7	.;M;M;.
PhyloP100		3.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D;D;D;.
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.37
MutPred		0.39		.;Gain of solvent accessibility (P = 1e-04);Gain of solvent accessibility (P = 1e-04);.;
MVP		0.29
MPC		0.58
ClinPred		0.46	T
GERP RS		5.5
Varity_R		0.68
gMVP		0.31
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs782683979; hg19: chrX-54224986;