22-41946436-A-C

Variant names:

• chr22-41946436-A-C
• rs751933875
• NM_024053.5:c.118T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024053.5(CENPM):​c.118T>G​(p.Cys40Gly) 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 1,460,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 2.12

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1507473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPM	NM_024053.5	c.118T>G	p.Cys40Gly	missense_variant	Exon 2 of 6	ENST00000215980.10	NP_076958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPM	ENST00000215980.10	c.118T>G	p.Cys40Gly	missense_variant	Exon 2 of 6	1	NM_024053.5	ENSP00000215980.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248884 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460680 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T;.;.;.;T
Eigen	Benign	0.029
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.0	M;.;.;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N;D;N;N;D
REVEL	Benign	0.12
Sift	Benign	0.32	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.
Vest4		0.37
MutPred		0.36		Gain of disorder (P = 0.0067);.;.;Gain of disorder (P = 0.0067);.;
MVP		0.59
MPC		0.43
ClinPred		0.75	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751933875; hg19: chr22-42342440;