rs146163970

Positions:

• chr22-50582319-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005198.5(CHKB):​c.263C>T​(p.Pro88Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,583,094 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: CHKB NM_005198.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.58

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHKB	NM_005198.5	c.263C>T	p.Pro88Leu	missense_variant	2/11	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.481C>T		non_coding_transcript_exon_variant	2/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938.3	c.263C>T	p.Pro88Leu	missense_variant	2/11	1	NM_005198.5	ENSP00000384400.3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000296 AC: 58 AN: 196110 Hom.: 0 AF XY: 0.000394 AC XY: 42 AN XY: 106466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00314

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000512

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000397

GnomAD4 exome AF: 0.000231 AC: 331 AN: 1430946 Hom.: 1 Cov.: 32 AF XY: 0.000258 AC XY: 183 AN XY: 709234

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.0000248

Gnomad4 ASJ exome AF: 0.00377

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.000325

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.000254

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000620

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.000202 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2024	Variant summary: CHKB c.263C>T (p.Pro88Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 196110 control chromosomes. c.263C>T has been reported in the literature in two siblings with Proximal Myopathy (Brady_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Megaconial Type Congenital Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26782016). ClinVar contains an entry for this variant (Variation ID: 447030). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2016	- -

Megaconial type congenital muscular dystrophy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 10, 2019	The CHKB c.263C>T (p.Pro88Leu) variant is a missense variant that has been reported in one study where it was identified in a compound heterozygous state with a second missense variant in two siblings who were diagnosed with proximal myopathy with focal depletion of mitochondria (Brady et al. 2016). The distinctive "oligomitochondrial" pattern with enlarged mitochondria around the periphery was observed in muscle biopsies from both patients. Control data are unavailable for this variant, which is reported at a frequency of 0.003146 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the limited evidence available, the p.Pro88Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for CHKB-related congenital muscular dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Uncertain	0.38
Sift	Benign	0.039	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.92
ClinPred		0.36	T
GERP RS		5.1
Varity_R		0.88
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs146163970; hg19: chr22-51020748;