rs527344657

Variant names:

• chr15-43698750-G-A
• rs527344657
• NM_001321926.2:c.1121G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-43698750-G-A
• chr15-43698750-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001321926.2(CKMT1A):​c.1121G>A​(p.Arg374Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,724 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 0.0 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CKMT1A NM_001321926.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

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.1121G>A	p.Arg374Gln	missense	Exon 8 of 9	NP_001308855.1	P12532-1
	CKMT1A	NM_001321927.1		c.1214G>A	p.Arg405Gln	missense	Exon 9 of 10	NP_001308856.1	P12532-2
	CKMT1A	NM_001321928.1		c.1214G>A	p.Arg405Gln	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.1121G>A	p.Arg374Gln	missense	Exon 8 of 9	ENSP00000406577.3	P12532-1
	CKMT1A	ENST00000909070.1		c.1214G>A	p.Arg405Gln	missense	Exon 9 of 10	ENSP00000579129.1
	CKMT1A	ENST00000909071.1		c.1214G>A	p.Arg405Gln	missense	Exon 9 of 10	ENSP00000579130.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151856 Hom.: 0 Cov.: 30

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: 0.00000795 AC: 2 AN: 251422 AF XY: 0.0000147

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: 0.000163

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461724 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727166

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111902

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151856 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74186

African (AFR) AF: 0.00 AC: 0 AN: 41282

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

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	0.99
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.1	T
PhyloP100		6.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.74
MutPred		0.93		Gain of ubiquitination at K377 (P = 0.1497)
MVP		0.36
MPC		1.0
ClinPred		0.99	D
GERP RS		2.0
Varity_R		0.86
gMVP		0.84
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs527344657; hg19: chr15-43990948;