chr22-41939124-C-A

Variant names:

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

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>T​(p.Gly159Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,572 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CENPM NM_024053.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• Publications: 0 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, 0.921

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>T	p.Gly159Cys	missense	Exon 6 of 6	NP_076958.1	Q9NSP4-1
	CENPM	NM_001304370.2		c.373G>T	p.Gly125Cys	missense	Exon 5 of 5	NP_001291299.1	B1AHQ6
	CENPM	NM_001110215.3		c.109G>T	p.Gly37Cys	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>T	p.Gly159Cys	missense	Exon 6 of 6	ENSP00000215980.5	Q9NSP4-1
	CENPM	ENST00000472374.6	TSL:1	c.109G>T	p.Gly37Cys	missense	Exon 2 of 2	ENSP00000430624.1	Q9NSP4-3
	CENPM	ENST00000921396.1		c.592G>T	p.Gly198Cys	missense	Exon 7 of 7	ENSP00000591455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460572 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726584

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.87		Gain of catalytic residue at P158 (P = 0.0134)
MVP		0.28
MPC		1.1
ClinPred		0.96	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.65
Mutation Taster		=80/20	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;