Genetic Variant CENPM:c.402+89C>A (chr22-41943521-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024053.5(CENPM):c.402+89C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 989,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.0000010 ( 0 hom. )

Consequence

CENPM
NM_024053.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.29

Publications

0 publications found

Variant links:

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]

CENPM links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CENPM	NM_024053.5	MANE Select	c.402+89C>A	intron	N/A	NP_076958.1	Q9NSP4-1
CENPM	NM_001304370.2		c.300+89C>A	intron	N/A	NP_001291299.1	B1AHQ6
CENPM	NM_001304372.2		c.*7+89C>A	intron	N/A	NP_001291301.1	B1AHQ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CENPM	ENST00000215980.10	TSL:1 MANE Select	c.402+89C>A	intron	N/A	ENSP00000215980.5	Q9NSP4-1
CENPM	ENST00000921396.1		c.519+89C>A	intron	N/A	ENSP00000591455.1
CENPM	ENST00000718240.1		c.300+89C>A	intron	N/A	ENSP00000520685.1	A0ABB0MV82

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000101

AC:

AN:

989256

Hom.:

AF XY:

0.00000201

AC XY:

AN XY:

498334

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23550

American (AMR)

AF:

0.00

AC:

AN:

32422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20386

East Asian (EAS)

AF:

0.00

AC:

AN:

33902

South Asian (SAS)

AF:

0.00

AC:

AN:

63044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3436

European-Non Finnish (NFE)

AF:

0.00000139

AC:

AN:

720066

Other (OTH)

AF:

0.00

AC:

AN:

44052

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.12

(source)

DANN

Benign

0.60

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over