15-43596490-A-T

Variant names:

• chr15-43596490-A-T
• rs772232119
• NM_001375484.1:c.835A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001375484.1(CKMT1B):​c.835A>T​(p.Met279Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,605,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CKMT1B NM_001375484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31
• Publications: 0 publications found

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

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=0.35460567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKMT1B	NM_001375484.1	c.835A>T	p.Met279Leu	missense_variant	Exon 6 of 9	ENST00000441322.6	NP_001362413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKMT1B	ENST00000441322.6	c.835A>T	p.Met279Leu	missense_variant	Exon 6 of 9	1	NM_001375484.1	ENSP00000413255.2

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147292 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

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: 0.0000240 AC: 6 AN: 250028 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458522 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725660

African (AFR) AF: 0.00 AC: 0 AN: 32552

American (AMR) AF: 0.000157 AC: 7 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 38546

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111310

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147292 Hom.: 0 Cov.: 26 AF XY: 0.0000139 AC XY: 1 AN XY: 71832

African (AFR) AF: 0.00 AC: 0 AN: 38076

American (AMR) AF: 0.000133 AC: 2 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 4798

South Asian (SAS) AF: 0.00 AC: 0 AN: 4712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67682

Other (OTH) AF: 0.00 AC: 0 AN: 2030

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.835A>T (p.M279L) alteration is located in exon 7 (coding exon 6) of the CKMT1B gene. This alteration results from a A to T substitution at nucleotide position 835, causing the methionine (M) at amino acid position 279 to be replaced by a leucine (L). 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	Benign	-0.27	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Benign	0.97
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Benign	0.27
Sift	Benign	0.061	T;T;.
Sift4G	Benign	0.78	T;T;T
Vest4		0.58
MutPred		0.63		Gain of methylation at K280 (P = 0.0374);Gain of methylation at K280 (P = 0.0374);Gain of methylation at K280 (P = 0.0374);
MVP		0.32
MPC		1.5
ClinPred		0.45	T
GERP RS		4.5
gMVP		0.72

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

Other links and lift over

dbSNP: rs772232119; hg19: chr15-43888688;