NM_001375484.1:c.742C>T

Variant names:

• chr15-43596282-C-T
• rs766693799
• NM_001375484.1:c.742C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001375484.1(CKMT1B):​c.742C>T​(p.Arg248Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 10)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CKMT1B NM_001375484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKMT1B	NM_001375484.1	c.742C>T	p.Arg248Cys	missense_variant	Exon 5 of 9	ENST00000441322.6	NP_001362413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKMT1B	ENST00000441322.6	c.742C>T	p.Arg248Cys	missense_variant	Exon 5 of 9	1	NM_001375484.1	ENSP00000413255.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 83550 Hom.: 0 Cov.: 10

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 90992 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000151 AC: 1 AN: 660356 Hom.: 0 Cov.: 9 AF XY: 0.00000294 AC XY: 1 AN XY: 340196

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16330

American (AMR) AF: 0.00 AC: 0 AN: 25644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16250

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30844

South Asian (SAS) AF: 0.00 AC: 0 AN: 53192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 447922

Other (OTH) AF: 0.00 AC: 0 AN: 32994

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 83550 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 38042

African (AFR) AF: 0.00 AC: 0 AN: 18564

American (AMR) AF: 0.00 AC: 0 AN: 7538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2474

East Asian (EAS) AF: 0.00 AC: 0 AN: 2592

South Asian (SAS) AF: 0.00 AC: 0 AN: 2106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 43564

Other (OTH) AF: 0.00 AC: 0 AN: 1004

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000976 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.742C>T (p.R248C) alteration is located in exon 6 (coding exon 5) of the CKMT1B gene. This alteration results from a C to T substitution at nucleotide position 742, causing the arginine (R) at amino acid position 248 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
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.32	T
PhyloP100		1.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.7	D;D;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.90
MutPred		0.95		Loss of MoRF binding (P = 0.1087);Loss of MoRF binding (P = 0.1087);Loss of MoRF binding (P = 0.1087);
MVP		0.74
MPC		2.2
ClinPred		1.0	D
GERP RS		4.3
gMVP		0.91

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: rs766693799; hg19: chr15-43888480;