19-45311762-C-A

Variant names:

• chr19-45311762-C-A
• rs1971111787
• NM_001824.5:c.640G>T

Variant summary

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

The NM_001824.5(CKM):​c.640G>T​(p.Ala214Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,990 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CKM NM_001824.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.55
• Publications: 0 publications found

Genes affected

CKM (HGNC:1994): (creatine kinase, M-type) The protein encoded by this gene is a cytoplasmic enzyme involved in energy homeostasis and is an important serum marker for myocardial infarction. The encoded protein reversibly catalyzes the transfer of phosphate between ATP and various phosphogens such as creatine phosphate. It acts as a homodimer in striated muscle as well as in other tissues, and as a heterodimer with a similar brain isozyme in heart. The encoded protein is a member of the ATP:guanido phosphotransferase protein family. [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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001824.5. 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
	CKM	NM_001824.5	MANE Select	c.640G>T	p.Ala214Ser	missense	Exon 5 of 8	NP_001815.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKM	ENST00000221476.4	TSL:1 MANE Select	c.640G>T	p.Ala214Ser	missense	Exon 5 of 8	ENSP00000221476.2	P06732
	CKM	ENST00000969560.1		c.640G>T	p.Ala214Ser	missense	Exon 5 of 8	ENSP00000639619.1
	CKM	ENST00000969562.1		c.757G>T	p.Ala253Ser	missense	Exon 6 of 9	ENSP00000639621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1434990 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 711678

⚠️ 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: 33276

American (AMR) AF: 0.00 AC: 0 AN: 41078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25560

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38946

South Asian (SAS) AF: 0.00 AC: 0 AN: 83476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099630

Other (OTH) AF: 0.00 AC: 0 AN: 59400

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.13	T
Sift4G	Benign	0.097	T
Polyphen		0.79	P
Vest4		0.47
MutPred		0.67		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.41
MPC		0.75
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.44
gMVP		0.82
Mutation Taster		=74/26	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: rs1971111787; hg19: chr19-45815020;