rs786205118

Variant names:

• chr22-50580564-C-G
• rs786205118
• NM_005198.5:c.677+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-50580564-C-G
• chr22-50580564-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_005198.5(CHKB):​c.677+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000547 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CHKB NM_005198.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.07
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08080808 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 27, new splice context is: atgGTaatg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50580564-C-G is Pathogenic according to our data. Variant chr22-50580564-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2165925.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHKB	NM_005198.5	c.677+1G>C		splice_donor_variant, intron_variant	Intron 5 of 10	ENST00000406938.3	NP_005189.2
CHKB-CPT1B	NR_027928.2	n.895+1G>C		splice_donor_variant, intron_variant	Intron 5 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHKB	ENST00000406938.3	c.677+1G>C		splice_donor_variant, intron_variant	Intron 5 of 10	1	NM_005198.5	ENSP00000384400.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megaconial type congenital muscular dystrophy Pathogenic:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with congenital muscular dystrophy (PMID: 21665002). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the CHKB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHKB are known to be pathogenic (PMID: 21665002). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.1
GERP RS		4.6
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: -26
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205118; hg19: chr22-51018993;