Genetic Variant CKB:p.Leu360Ile (chr14-103519932-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001823.5(CKB):c.1078C>A(p.Leu360Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CKB
NM_001823.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.74

Publications

0 publications found

Variant links:

Genes affected

CKB (HGNC:1991): (creatine kinase B) The protein encoded by this gene is a cytoplasmic enzyme involved in energy homeostasis. The encoded protein reversibly catalyzes the transfer of phosphate between ATP and various phosphogens such as creatine phosphate. It acts as a homodimer in brain as well as in other tissues, and as a heterodimer with a similar muscle isozyme in heart. The encoded protein is a member of the ATP:guanido phosphotransferase protein family. A pseudogene of this gene has been characterized. [provided by RefSeq, Jul 2008]

CKB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4120626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKB	NM_001823.5 link	c.1078C>A	p.Leu360Ile	missense_variant	Exon 8 of 8	ENST00000348956.7	NP_001814.2
CKB	NM_001362531.2 link	c.1150C>A	p.Leu384Ile	missense_variant	Exon 7 of 7		NP_001349460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKB	ENST00000348956.7 link	c.1078C>A	p.Leu360Ile	missense_variant	Exon 8 of 8	1	NM_001823.5	ENSP00000299198.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457600

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111930

Other (OTH)

AF:

0.00

AC:

AN:

60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

L;.

PhyloP100

4.7

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.18

Sift

Benign

0.16

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.59

P;.

Vest4

0.36

MutPred

0.50

Gain of catalytic residue at V357 (P = 0.0633);.;

MVP

0.39

MPC

1.5

ClinPred

0.82

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.78

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over