9-93289548-CG-C

Variant names:

• chr9-93289548-CG-C
• rs757473977
• NM_006648.4:c.4801delG

Variant summary

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

The NM_006648.4(WNK2):​c.4801delG​(p.Asp1601ThrfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000495 in 1,414,868 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: WNK2 NM_006648.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• Publications: 0 publications found

Genes affected

WNK2 (HGNC:14542): (WNK lysine deficient protein kinase 2) The protein encoded by this gene is a cytoplasmic serine-threonine kinase that belongs to the protein kinase superfamily. The protein plays an important role in the regulation of electrolyte homeostasis, cell signaling survival, and proliferation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006648.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK2	NM_006648.4	MANE Select	c.4801delG	p.Asp1601ThrfsTer35	frameshift	Exon 20 of 30	NP_006639.3
	WNK2	NM_001282394.3		c.4912delG	p.Asp1638ThrfsTer35	frameshift	Exon 21 of 31	NP_001269323.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNK2	ENST00000427277.7	TSL:5 MANE Select	c.4801delG	p.Asp1601ThrfsTer35	frameshift	Exon 20 of 30	ENSP00000411181.4
	WNK2	ENST00000297954.9	TSL:1	c.4912delG	p.Asp1638ThrfsTer35	frameshift	Exon 21 of 31	ENSP00000297954.4
	WNK2	ENST00000432730.6	TSL:1	c.4801delG	p.Asp1601ThrfsTer35	frameshift	Exon 19 of 29	ENSP00000415038.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000495 AC: 7 AN: 1414868 Hom.: 0 Cov.: 35 AF XY: 0.00000860 AC XY: 6 AN XY: 697414

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32490

American (AMR) AF: 0.00 AC: 0 AN: 40998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24238

East Asian (EAS) AF: 0.00 AC: 0 AN: 38786

South Asian (SAS) AF: 0.0000244 AC: 2 AN: 81950

European-Finnish (FIN) AF: 0.0000214 AC: 1 AN: 46804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1085738

Other (OTH) AF: 0.0000172 AC: 1 AN: 58278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.9
Mutation Taster		=13/187	disease causing (fs/PTC)

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: rs757473977; hg19: chr9-96051830; COSMIC: COSV52940721; COSMIC: COSV52940721;