16-81017333-A-C

Variant names:

Variant summary

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

The NM_001100624.3(CENPN):c.225A>C(p.Gln75His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000789 in 1,596,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

CENPN
NM_001100624.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.576

Publications

2 publications found

Variant links:

Genes affected

CENPN (HGNC:30873): (centromere protein N) The protein encoded by this gene forms part of the nucleosome-associated complex and is important for kinetochore assembly. It is bound to kinetochores during S phase and G2 and recruits other proteins to the centromere. Pseudogenes of this gene are located on chromosome 2. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]

CENPN links:

CMC2 (HGNC:24447): (C-X9-C motif containing 2) Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

CMC2 links:

CENPN-AS1 (HGNC:55106): (CENPN antisense RNA 1)

CENPN-AS1 links:

Genome browser will be placed here

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 (MetaRNN=0.059260517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPN	NM_001100624.3 link	c.225A>C	p.Gln75His	missense_variant	Exon 4 of 11	ENST00000305850.10	NP_001094094.2	Q96H22-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPN	ENST00000305850.10 link	c.225A>C	p.Gln75His	missense_variant	Exon 4 of 11	1	NM_001100624.3	ENSP00000305608.5		Q96H22-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

250622

AF XY:

0.00000738

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000845

AC:

122

AN:

1443944

Hom.:

Cov.:

AF XY:

0.0000820

AC XY:

AN XY:

719510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33090

American (AMR)

AF:

0.00

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.00

AC:

AN:

85674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.000109

AC:

119

AN:

1096318

Other (OTH)

AF:

0.0000502

AC:

AN:

59794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.225A>C (p.Q75H) alteration is located in exon 4 (coding exon 3) of the CENPN gene. This alteration results from a A to C substitution at nucleotide position 225, causing the glutamine (Q) at amino acid position 75 to be replaced by a histidine (H). 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

0.45

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.94

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0069

T;.;.;.;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.059

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

L;L;L;L;.

PhyloP100

-0.58

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.048

Sift

Benign

0.69

T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T

Polyphen

0.016

B;B;.;.;.

Vest4

0.19

MutPred

0.64

Loss of catalytic residue at Q75 (P = 0.0601);Loss of catalytic residue at Q75 (P = 0.0601);Loss of catalytic residue at Q75 (P = 0.0601);Loss of catalytic residue at Q75 (P = 0.0601);Loss of catalytic residue at Q75 (P = 0.0601);

MVP

0.12

MPC

0.028

ClinPred

0.036

GERP RS

-0.54

PromoterAI

-0.0084

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.087

gMVP

0.32

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

16-81017333-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over