15-43598241-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001375484.1(CKMT1B):​c.925C>T​(p.Arg309Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000933 in 1,607,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CKMT1B
NM_001375484.1 missense

Scores

4
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

Publications

0 publications found
Variant links:
Genes affected
CKMT1B (HGNC:1995): (creatine kinase, mitochondrial 1B) Mitochondrial creatine (MtCK) kinase is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. It belongs to the creatine kinase isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Many malignant cancers with poor prognosis have shown overexpression of ubiquitous mitochondrial creatine kinase; this may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. Ubiquitous mitochondrial creatine kinase has 80% homology with the coding exons of sarcomeric mitochondrial creatine kinase. Two genes located near each other on chromosome 15 have been identified which encode identical mitochondrial creatine kinase proteins. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CKMT1BNM_001375484.1 linkc.925C>T p.Arg309Cys missense_variant Exon 7 of 9 ENST00000441322.6 NP_001362413.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CKMT1BENST00000441322.6 linkc.925C>T p.Arg309Cys missense_variant Exon 7 of 9 1 NM_001375484.1 ENSP00000413255.2 P12532-1
CKMT1BENST00000300283.10 linkc.925C>T p.Arg309Cys missense_variant Exon 8 of 10 5 ENSP00000300283.6 P12532-1
CKMT1BENST00000437534.3 linkn.*845C>T non_coding_transcript_exon_variant Exon 7 of 9 2 ENSP00000416717.1 F8WCN3
CKMT1BENST00000437534.3 linkn.*845C>T 3_prime_UTR_variant Exon 7 of 9 2 ENSP00000416717.1 F8WCN3

Frequencies

GnomAD3 genomes
AF:
0.0000134
AC:
2
AN:
148908
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000513
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
250124
AF XY:
0.00000740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000891
AC:
13
AN:
1458736
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
725772
show subpopulations
African (AFR)
AF:
0.0000307
AC:
1
AN:
32542
American (AMR)
AF:
0.00
AC:
0
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38580
South Asian (SAS)
AF:
0.0000929
AC:
8
AN:
86130
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53264
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5756
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111418
Other (OTH)
AF:
0.00
AC:
0
AN:
60236
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000134
AC:
2
AN:
148908
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
1
AN XY:
72680
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000513
AC:
2
AN:
38996
American (AMR)
AF:
0.00
AC:
0
AN:
15150
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4940
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4782
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67910
Other (OTH)
AF:
0.00
AC:
0
AN:
2050
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000868
Hom.:
0
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 02, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.925C>T (p.R309C) alteration is located in exon 8 (coding exon 7) of the CKMT1B gene. This alteration results from a C to T substitution at nucleotide position 925, causing the arginine (R) at amino acid position 309 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
27
DANN
Pathogenic
1.0
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.87
D
M_CAP
Benign
0.051
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Benign
-0.91
T
PhyloP100
1.5
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.7
D;D
REVEL
Uncertain
0.41
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.040
D;D
Vest4
0.82
MutPred
0.74
Loss of catalytic residue at R309 (P = 0.0473);Loss of catalytic residue at R309 (P = 0.0473);
MVP
0.53
MPC
2.2
ClinPred
0.97
D
GERP RS
4.4
gMVP
0.70
Mutation Taster
=18/82
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs767576863; hg19: chr15-43890439; API