5-81251166-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001099735.2(CKMT2):c.34C>T(p.Arg12Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,910 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CKMT2
NM_001099735.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.24

Variant links:

Genes affected

CKMT2 (HGNC:1996): (creatine kinase, mitochondrial 2) Mitochondrial creatine kinase (MtCK) 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. Sarcomeric mitochondrial creatine kinase has 80% homology with the coding exons of ubiquitous mitochondrial creatine kinase. This gene contains sequences homologous to several motifs that are shared among some nuclear genes encoding mitochondrial proteins and thus may be essential for the coordinated activation of these genes during mitochondrial biogenesis. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

CKMT2 links:

CKMT2-AS1 (HGNC:48997): (CKMT2 antisense RNA 1)

CKMT2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKMT2	NM_001099735.2 link	c.34C>T	p.Arg12Cys	missense_variant	Exon 2 of 10	ENST00000254035.9	NP_001093205.1	P17540A0A024RAK5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKMT2	ENST00000254035.9 link	c.34C>T	p.Arg12Cys	missense_variant	Exon 2 of 10	1	NM_001099735.2	ENSP00000254035.4		P17540

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251352

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135838

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>T (p.R12C) alteration is located in exon 3 (coding exon 1) of the CKMT2 gene. This alteration results from a C to T substitution at nucleotide position 34, causing the arginine (R) at amino acid position 12 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

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;.;T;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D;D;.;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.2

M;.;M;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.020

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.84

MutPred

0.74

Loss of methylation at R12 (P = 0.016);Loss of methylation at R12 (P = 0.016);Loss of methylation at R12 (P = 0.016);Loss of methylation at R12 (P = 0.016);Loss of methylation at R12 (P = 0.016);

MVP

0.91

MPC

0.96

ClinPred

0.95

GERP RS

5.5

Varity_R

0.30

gMVP

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over