22-50578965-G-C

Position:

• chr22-50578965-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005198.5(CHKB):​c.*216C>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0956 in 608,108 control chromosomes in the GnomAD database, including 5,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1191 hom., cov: 32)
  • Exomes 𝑓: 0.094 (3822 hom.)
• Consequence: CHKB NM_005198.5 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.85

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:):

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 22-50578965-G-C is Benign according to our data. Variant chr22-50578965-G-C is described in ClinVar as [Benign]. Clinvar id is 342160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50578965-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHKB	NM_005198.5	c.*216C>G		splice_region_variant	11/11	ENST00000406938.3	NP_005189.2
CHKB	NM_005198.5	c.*216C>G		3_prime_UTR_variant	11/11	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.1551+71C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938.3	c.*216C>G		splice_region_variant	11/11	1	NM_005198.5	ENSP00000384400.3
CHKB	ENST00000406938	c.*216C>G		3_prime_UTR_variant	11/11	1	NM_005198.5	ENSP00000384400.3
CHKB-CPT1B	ENST00000453634.5	n.*145+71C>G		intron_variant		5		ENSP00000457031.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15369 AN: 152084 Hom.: 1188 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0526

Gnomad OTH AF: 0.0835

GnomAD4 exome AF: 0.0938 AC: 42748 AN: 455906 Hom.: 3822 Cov.: 4 AF XY: 0.0956 AC XY: 23137 AN XY: 242052

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0518

Gnomad4 EAS exome AF: 0.373

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.0666

Gnomad4 NFE exome AF: 0.0517

Gnomad4 OTH exome AF: 0.0879

GnomAD4 genome AF: 0.101 AC: 15405 AN: 152202 Hom.: 1191 Cov.: 32 AF XY: 0.106 AC XY: 7865 AN XY: 74424

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0712

Gnomad4 NFE AF: 0.0526

Gnomad4 OTH AF: 0.0859

Alfa AF: 0.0731 Hom.: 97

Bravo AF: 0.109

Asia WGS AF: 0.257 AC: 894 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -

Megaconial type congenital muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3180872; hg19: chr22-51017394;