22-50582333-G-T

Variant names:

• chr22-50582333-G-T
• rs180979987
• NM_005198.5:c.249C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000406938.3(CHKB):​c.249C>A​(p.Phe83Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000703 in 1,421,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F83F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CHKB ENST00000406938.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.59
• Publications: 0 publications found

Genes affected

CHKB (HGNC:1938): (choline kinase beta) Choline kinase (CK) and ethanolamine kinase (EK) catalyze the phosphorylation of choline/ethanolamine to phosphocholine/phosphoethanolamine. This is the first enzyme in the biosynthesis of phosphatidylcholine/phosphatidylethanolamine in all animal cells. The highly purified CKs from mammalian sources and their recombinant gene products have been shown to have EK activity also, indicating that both activities reside on the same protein. The choline kinase-like protein encoded by CHKL belongs to the choline/ethanolamine kinase family; however, its exact function is not known. Read-through transcripts are expressed from this locus that include exons from the downstream CPT1B locus. [provided by RefSeq, Jun 2009]

CHKB-CPT1B (HGNC:41998): (CHKB-CPT1B readthrough (NMD candidate)) The genes CHKB and CPT1B are adjacent on chromosome 22 and read-through transcripts are expressed that include exons from both loci. The read-through transcripts are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to express proteins. [provided by RefSeq, Jun 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000406938.3. 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
	CHKB	NM_005198.5	MANE Select	c.249C>A	p.Phe83Leu	missense	Exon 2 of 11	NP_005189.2
	CHKB-CPT1B	NR_027928.2		n.467C>A		non_coding_transcript_exon	Exon 2 of 30

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHKB	ENST00000406938.3	TSL:1 MANE Select	c.249C>A	p.Phe83Leu	missense	Exon 2 of 11	ENSP00000384400.3
	CHKB	ENST00000481673.5	TSL:1	n.313C>A		non_coding_transcript_exon	Exon 2 of 10
	CHKB	ENST00000463053.1	TSL:3	n.331C>A		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1421758 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 703952

African (AFR) AF: 0.00 AC: 0 AN: 32746

American (AMR) AF: 0.00 AC: 0 AN: 38940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 37956

South Asian (SAS) AF: 0.00 AC: 0 AN: 81014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4302

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094426

Other (OTH) AF: 0.00 AC: 0 AN: 58804

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.033
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.18
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.017	D
Polyphen		0.25	B
Vest4		0.72
MutPred		0.72		Loss of sheet (P = 0.1158)
MVP		0.67
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.55
gMVP		0.82
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs180979987; hg19: chr22-51020762;