rs141381896

Positions:

• chr22-50579775-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005198.5(CHKB):​c.983A>G​(p.Gln328Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,614,094 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (23 hom.)
• Consequence: CHKB NM_005198.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.178

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036141276).
• BP6: Variant 22-50579775-T-C is Benign according to our data. Variant chr22-50579775-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128730.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr22-50579775-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00335 (510/152306) while in subpopulation SAS AF= 0.00663 (32/4828). AF 95% confidence interval is 0.00491. There are 1 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHKB	NM_005198.5	c.983A>G	p.Gln328Arg	missense_variant	9/11	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.1201A>G		non_coding_transcript_exon_variant	9/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938.3	c.983A>G	p.Gln328Arg	missense_variant	9/11	1	NM_005198.5	ENSP00000384400	P1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 515 AN: 152186 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00410 AC: 1021 AN: 248986 Hom.: 6 AF XY: 0.00427 AC XY: 575 AN XY: 134800

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00617

Gnomad FIN exome AF: 0.000972

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00485 AC: 7090 AN: 1461788 Hom.: 23 Cov.: 32 AF XY: 0.00496 AC XY: 3604 AN XY: 727206

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00624

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00527

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74474

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00536

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00521 Hom.: 8

Bravo AF: 0.00333

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00407 AC: 494

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00742

EpiControl AF: 0.00676

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 10, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CHKB: BP4, BS2 -

Megaconial type congenital muscular dystrophy Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.8
DANN	Benign	0.70
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.042
Sift	Benign	0.53	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.29
ClinPred		0.00058	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs141381896; hg19: chr22-51018204;