rs139818555

Variant names:

• chr22-50581420-C-G
• rs139818555
• NM_005198.5:c.581G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-50581420-C-G
• chr22-50581420-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_005198.5(CHKB):​c.581G>C​(p.Arg194Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R194Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHKB NM_005198.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50581420-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 573092.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHKB	NM_005198.5	c.581G>C	p.Arg194Pro	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.799G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938.3	c.581G>C	p.Arg194Pro	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_005198.5	ENSP00000384400.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.054	T
Polyphen		0.055	B
Vest4		0.81
MutPred		0.67		Loss of ubiquitination at K197 (P = 0.0589);
MVP		0.80
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.94
gMVP		0.88
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.16		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: rs139818555; hg19: chr22-51019849;