15-43598912-T-C

Variant names:

• chr15-43598912-T-C
• rs150307940
• NM_001375484.1:c.1097T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001375484.1(CKMT1B):​c.1097T>C​(p.Val366Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,609,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CKMT1B NM_001375484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.813
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKMT1B	NM_001375484.1	c.1097T>C	p.Val366Ala	missense_variant	Exon 8 of 9	ENST00000441322.6	NP_001362413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKMT1B	ENST00000441322.6	c.1097T>C	p.Val366Ala	missense_variant	Exon 8 of 9	1	NM_001375484.1	ENSP00000413255.2
CKMT1B	ENST00000300283.10	c.1097T>C	p.Val366Ala	missense_variant	Exon 9 of 10	5		ENSP00000300283.6
CKMT1B	ENST00000437534.3	n.*1017T>C		non_coding_transcript_exon_variant	Exon 8 of 9	2		ENSP00000416717.1
CKMT1B	ENST00000437534.3	n.*1017T>C		3_prime_UTR_variant	Exon 8 of 9	2		ENSP00000416717.1

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 149710 Hom.: 0 Cov.: 29

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250796 AF XY: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460184 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726496

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39202

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111780

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 149710 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73038

African (AFR) AF: 0.00 AC: 0 AN: 39718

American (AMR) AF: 0.00 AC: 0 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4964

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67878

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1097T>C (p.V366A) alteration is located in exon 9 (coding exon 8) of the CKMT1B gene. This alteration results from a T to C substitution at nucleotide position 1097, causing the valine (V) at amino acid position 366 to be replaced by an alanine (A). 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	-0.20	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.79	T
PhyloP100		0.81
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.065	T;T
Vest4		0.58
MVP		0.38
MPC		1.2
ClinPred		0.26	T
GERP RS		0.59
gMVP		0.59
Mutation Taster		=78/22	polymorphism

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: rs150307940; hg19: chr15-43891110;