NM_024053.5:c.32C>G

Variant names:

• chr22-41947045-G-C
• rs2077814493
• NM_024053.5:c.32C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024053.5(CENPM):​c.32C>G​(p.Pro11Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CENPM NM_024053.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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]

SMIM45 (HGNC:27930): (small integral membrane protein 45) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPM	NM_024053.5	c.32C>G	p.Pro11Arg	missense_variant	Exon 1 of 6	ENST00000215980.10	NP_076958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPM	ENST00000215980.10	c.32C>G	p.Pro11Arg	missense_variant	Exon 1 of 6	1	NM_024053.5	ENSP00000215980.5
CENPM	ENST00000407253.7	c.32C>G	p.Pro11Arg	missense_variant	Exon 1 of 5	2		ENSP00000384743.3
CENPM	ENST00000396437.3	n.107C>G		non_coding_transcript_exon_variant	Exon 1 of 4	3
CENPM	ENST00000460824.1	n.89C>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32C>G (p.P11R) alteration is located in exon 1 (coding exon 1) of the CENPM gene. This alteration results from a C to G substitution at nucleotide position 32, causing the proline (P) at amino acid position 11 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
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.73		Gain of MoRF binding (P = 0.0169);Gain of MoRF binding (P = 0.0169);
MVP		0.36
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs2077814493; hg19: chr22-42343049;