22-50579085-C-G

Position:

• chr22-50579085-C-G

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.*96G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,231,266 control chromosomes in the GnomAD database, including 1,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (195 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1452 hom.)
• Consequence: CHKB NM_005198.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.182

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]

CHKB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 22-50579085-C-G is Benign according to our data. Variant chr22-50579085-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 342164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHKB	NM_005198.5	c.*96G>C		3_prime_UTR_variant	11/11	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.1502G>C		non_coding_transcript_exon_variant	11/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938	c.*96G>C		3_prime_UTR_variant	11/11	1	NM_005198.5	ENSP00000384400.3
CHKB-CPT1B	ENST00000453634.5	n.*96G>C		non_coding_transcript_exon_variant	3/23	5		ENSP00000457031.1
CHKB-CPT1B	ENST00000453634.5	n.*96G>C		3_prime_UTR_variant	3/23	5		ENSP00000457031.1

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5401 AN: 152182 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0755

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0388

GnomAD4 exome AF: 0.0369 AC: 39767 AN: 1078966 Hom.: 1452 Cov.: 15 AF XY: 0.0400 AC XY: 21844 AN XY: 546558

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.0803

Gnomad4 ASJ exome AF: 0.0335

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0520

Gnomad4 NFE exome AF: 0.0229

Gnomad4 OTH exome AF: 0.0388

GnomAD4 genome AF: 0.0355 AC: 5408 AN: 152300 Hom.: 195 Cov.: 32 AF XY: 0.0407 AC XY: 3034 AN XY: 74458

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.0754

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.0586

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0284 Hom.: 14

Bravo AF: 0.0325

Asia WGS AF: 0.130 AC: 449 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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	-0.62
CADD	Benign	9.4
DANN	Benign	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: rs17001634; hg19: chr22-51017514;