15-43698687-G-T

Variant names:

• chr15-43698687-G-T
• rs377040828
• NM_001321926.2:c.1058G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001321926.2(CKMT1A):​c.1058G>T​(p.Arg353Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,440 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: 29)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CKMT1A NM_001321926.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59
• Publications: 5 publications found

Genes affected

CKMT1A (HGNC:31736): (creatine kinase, mitochondrial 1A) 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321926.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKMT1A	NM_001321926.2	MANE Select	c.1058G>T	p.Arg353Leu	missense	Exon 8 of 9	NP_001308855.1	P12532-1
	CKMT1A	NM_001321927.1		c.1151G>T	p.Arg384Leu	missense	Exon 9 of 10	NP_001308856.1	P12532-2
	CKMT1A	NM_001321928.1		c.1151G>T	p.Arg384Leu	missense	Exon 9 of 10	NP_001308857.1	P12532-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKMT1A	ENST00000413453.7	TSL:1 MANE Select	c.1058G>T	p.Arg353Leu	missense	Exon 8 of 9	ENSP00000406577.3	P12532-1
	CKMT1A	ENST00000909070.1		c.1151G>T	p.Arg384Leu	missense	Exon 9 of 10	ENSP00000579129.1
	CKMT1A	ENST00000909071.1		c.1151G>T	p.Arg384Leu	missense	Exon 9 of 10	ENSP00000579130.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151742 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000485

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

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461698 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727140

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151742 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74126

African (AFR) AF: 0.0000485 AC: 2 AN: 41248

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.0	T
PhyloP100		6.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Vest4		0.88
MVP		0.39
MPC		1.0
ClinPred		1.0	D
GERP RS		2.5
Varity_R		0.92
gMVP		0.92
Mutation Taster		=41/59	disease causing

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: rs377040828; hg19: chr15-43990885;