22-50579047-A-G

Variant names:

• chr22-50579047-A-G
• rs1056964
• NM_005198.5:c.*134T>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.*134T>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 0.0898 in 847,002 control chromosomes in the GnomAD database, including 6,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1210 hom., cov: 32)
  • Exomes 𝑓: 0.087 (4912 hom.)
• Consequence: CHKB NM_005198.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.23

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 22-50579047-A-G is Benign according to our data. Variant chr22-50579047-A-G is described in ClinVar as [Benign]. Clinvar id is 342162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50579047-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHKB	NM_005198.5	c.*134T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.1540T>C		non_coding_transcript_exon_variant	Exon 11 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938	c.*134T>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_005198.5	ENSP00000384400.3
CHKB-CPT1B	ENST00000453634.5	n.*134T>C		non_coding_transcript_exon_variant	Exon 3 of 23	5		ENSP00000457031.1
CHKB-CPT1B	ENST00000453634.5	n.*134T>C		3_prime_UTR_variant	Exon 3 of 23	5		ENSP00000457031.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15424 AN: 152110 Hom.: 1207 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0526

Gnomad OTH AF: 0.0832

GnomAD4 exome AF: 0.0872 AC: 60592 AN: 694774 Hom.: 4912 Cov.: 9 AF XY: 0.0887 AC XY: 32414 AN XY: 365472

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.0536

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.0681

Gnomad4 NFE exome AF: 0.0522

Gnomad4 OTH exome AF: 0.0893

GnomAD4 genome AF: 0.102 AC: 15458 AN: 152228 Hom.: 1210 Cov.: 32 AF XY: 0.106 AC XY: 7895 AN XY: 74444

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.0713

Gnomad4 NFE AF: 0.0526

Gnomad4 OTH AF: 0.0856

Alfa AF: 0.0668 Hom.: 217

Bravo AF: 0.109

Asia WGS AF: 0.256 AC: 891 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	clinical testing	GeneDx	Jun 28, 2018	- -
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	-0.93
CADD	Benign	1.6
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1056964; hg19: chr22-51017476;