chr15-43596479-A-G

Variant names:

• chr15-43596479-A-G
• rs149230297
• NM_001375484.1:c.824A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001375484.1(CKMT1B):​c.824A>G​(p.Lys275Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,603,876 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 26)
  • Exomes 𝑓: 0.00049 (11 hom.)
• Consequence: CKMT1B NM_001375484.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKMT1B	NM_001375484.1	c.824A>G	p.Lys275Arg	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.824A>G	p.Lys275Arg	missense_variant	Exon 6 of 9	1	NM_001375484.1	ENSP00000413255.2

Frequencies

GnomAD3 genomes AF: 0.000212 AC: 31 AN: 146436 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.0000266

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: 0.000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000212 AC: 53 AN: 249816 AF XY: 0.000229

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: 0.000468

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000486 AC: 708 AN: 1457440 Hom.: 11 Cov.: 31 AF XY: 0.000452 AC XY: 328 AN XY: 725212

African (AFR) AF: 0.00 AC: 0 AN: 32418

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 38504

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000610 AC: 677 AN: 1110490

Other (OTH) AF: 0.000515 AC: 31 AN: 60160

GnomAD4 genome AF: 0.000212 AC: 31 AN: 146436 Hom.: 1 Cov.: 26 AF XY: 0.000112 AC XY: 8 AN XY: 71346

African (AFR) AF: 0.0000266 AC: 1 AN: 37600

American (AMR) AF: 0.00 AC: 0 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4752

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10180

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

European-Non Finnish (NFE) AF: 0.000444 AC: 30 AN: 67572

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000256 AC: 31

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.824A>G (p.K275R) alteration is located in exon 7 (coding exon 6) of the CKMT1B gene. This alteration results from a A to G substitution at nucleotide position 824, causing the lysine (K) at amino acid position 275 to be replaced by an arginine (R). 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	-0.28	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.89	T
PhyloP100		9.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.011	D;D;.
Sift4G	Uncertain	0.027	D;D;D
Vest4		0.67
MVP		0.61
MPC		0.74
ClinPred		0.36	T
GERP RS		4.5
gMVP		0.61
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149230297; hg19: chr15-43888677;