chr14-103522318-G-A

Variant names:

• chr14-103522318-G-A
• rs11545344
• NM_001823.5:c.176C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001823.5(CKB):​c.176C>T​(p.Thr59Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CKB NM_001823.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.40
• Publications: 2 publications found

Genes affected

CKB (HGNC:1991): (creatine kinase B) The protein encoded by this gene is a cytoplasmic enzyme involved in energy homeostasis. The encoded protein reversibly catalyzes the transfer of phosphate between ATP and various phosphogens such as creatine phosphate. It acts as a homodimer in brain as well as in other tissues, and as a heterodimer with a similar muscle isozyme in heart. The encoded protein is a member of the ATP:guanido phosphotransferase protein family. A pseudogene of this gene has been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001823.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKB	NM_001823.5	MANE Select	c.176C>T	p.Thr59Ile	missense	Exon 2 of 8	NP_001814.2
	CKB	NM_001362531.2		c.176C>T	p.Thr59Ile	missense	Exon 2 of 7	NP_001349460.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CKB	ENST00000348956.7	TSL:1 MANE Select	c.176C>T	p.Thr59Ile	missense	Exon 2 of 8	ENSP00000299198.2
	CKB	ENST00000689346.1		c.176C>T	p.Thr59Ile	missense	Exon 2 of 7	ENSP00000508488.1
	CKB	ENST00000553878.5	TSL:2	c.176C>T	p.Thr59Ile	missense	Exon 1 of 4	ENSP00000451904.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.63		Gain of catalytic residue at D62 (P = 0)
MVP		0.61
MPC		2.2
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.92
Mutation Taster		=31/69	disease causing

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: rs11545344; hg19: chr14-103988655;