22-41939124-C-G

Variant names:

• chr22-41939124-C-G
• rs774792724
• NM_024053.5:c.475G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024053.5(CENPM):​c.475G>C​(p.Gly159Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. G159S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CENPM NM_024053.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• Publications: 1 publications found

Genes affected

CENPM (HGNC:18352): (centromere protein M) The protein encoded by this gene is an inner protein of the kinetochore, the multi-protein complex that binds spindle microtubules to regulate chromosome segregation during cell division. It belongs to the constitutive centromere-associated network protein group, whose members interact with outer kinetochore proteins and help to maintain centromere identity at each cell division cycle. The protein is structurally related to GTPases but cannot bind guanosine triphosphate. A point mutation that affects interaction with another constitutive centromere-associated network protein, CENP-I, impairs kinetochore assembly and chromosome alignment, suggesting that it is required for kinetochore formation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024053.5. 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
	CENPM	NM_024053.5	MANE Select	c.475G>C	p.Gly159Arg	missense	Exon 6 of 6	NP_076958.1	Q9NSP4-1
	CENPM	NM_001304370.2		c.373G>C	p.Gly125Arg	missense	Exon 5 of 5	NP_001291299.1	B1AHQ6
	CENPM	NM_001110215.3		c.109G>C	p.Gly37Arg	missense	Exon 2 of 2	NP_001103685.1	Q9NSP4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPM	ENST00000215980.10	TSL:1 MANE Select	c.475G>C	p.Gly159Arg	missense	Exon 6 of 6	ENSP00000215980.5	Q9NSP4-1
	CENPM	ENST00000472374.6	TSL:1	c.109G>C	p.Gly37Arg	missense	Exon 2 of 2	ENSP00000430624.1	Q9NSP4-3
	CENPM	ENST00000921396.1		c.592G>C	p.Gly198Arg	missense	Exon 7 of 7	ENSP00000591455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.84		Gain of MoRF binding (P = 0.0343)
MVP		0.27
MPC		1.2
ClinPred		0.93	D
GERP RS		3.4
Varity_R		0.38
gMVP		0.63
Mutation Taster		=84/16	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: rs774792724; hg19: chr22-42335128;