22-50578973-A-C

Position:

• chr22-50578973-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005198.5(CHKB):​c.*208T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 618,208 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (9 hom.)
• Consequence: CHKB NM_005198.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.100

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:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00466 (709/152252) while in subpopulation AFR AF= 0.0071 (295/41542). AF 95% confidence interval is 0.00643. There are 1 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHKB	NM_005198.5	c.*208T>G		3_prime_UTR_variant	11/11	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.1551+63T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938.3	c.*208T>G		3_prime_UTR_variant	11/11	1	NM_005198.5	ENSP00000384400	P1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 709 AN: 152134 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00400 AC: 1865 AN: 465956 Hom.: 9 Cov.: 4 AF XY: 0.00404 AC XY: 998 AN XY: 247332

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.00481

Gnomad4 FIN exome AF: 0.000294

Gnomad4 NFE exome AF: 0.00461

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00466 AC: 709 AN: 152252 Hom.: 1 Cov.: 33 AF XY: 0.00450 AC XY: 335 AN XY: 74440

Gnomad4 AFR AF: 0.00710

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00493

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.00486

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Megaconial type congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.1
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: rs41281533; hg19: chr22-51017402;