15-43596460-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001375484.1(CKMT1B):c.805C>T(p.Arg269Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,595,962 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 0.000042 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CKMT1B NM_001375484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.609

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CKMT1B	NM_001375484.1	c.805C>T	p.Arg269Trp	missense_variant	6/9	ENST00000441322.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CKMT1B	ENST00000441322.6	c.805C>T	p.Arg269Trp	missense_variant	6/9	1	NM_001375484.1	P1
CKMT1B	ENST00000300283.10	c.805C>T	p.Arg269Trp	missense_variant	7/10	5		P1
CKMT1B	ENST00000627381.1	c.805C>T	p.Arg269Trp	missense_variant	6/7	5
CKMT1B	ENST00000437534.3	c.805C>T	p.Arg269Trp	missense_variant, NMD_transcript_variant	6/9	2

Frequencies

GnomAD3 genomes AF: 0.0000416 AC: 6 AN: 144350 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000522 AC: 13 AN: 248928 Hom.: 0 AF XY: 0.0000668 AC XY: 9 AN XY: 134716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 41 AN: 1451506 Hom.: 0 Cov.: 29 AF XY: 0.0000304 AC XY: 22 AN XY: 722546

Gnomad4 AFR exome AF: 0.0000626

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000415 AC: 6 AN: 144456 Hom.: 0 Cov.: 25 AF XY: 0.0000427 AC XY: 3 AN XY: 70282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000101

Gnomad4 NFE AF: 0.0000297

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.805C>T (p.R269W) alteration is located in exon 7 (coding exon 6) of the CKMT1B gene. This alteration results from a C to T substitution at nucleotide position 805, causing the arginine (R) at amino acid position 269 to be replaced by a tryptophan (W). 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	0.092	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.6	D;D;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.028	D;D;D
Vest4		0.93
MutPred		0.94		Loss of disorder (P = 0.0259);Loss of disorder (P = 0.0259);Loss of disorder (P = 0.0259);
MVP		0.61
MPC		2.0
ClinPred		1.0	D
GERP RS		1.4
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs749828844; hg19: chr15-43888658;