rs141321114

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001813.3(CENPE):c.7886G>A(p.Arg2629Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,828 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

CENPE
NM_001813.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -1.93

Publications

9 publications found

Variant links:

Genes affected

CENPE (HGNC:1856): (centromere protein E) Centrosome-associated protein E (CENPE) is a kinesin-like motor protein that accumulates in the G2 phase of the cell cycle. Unlike other centrosome-associated proteins, it is not present during interphase and first appears at the centromere region of chromosomes during prometaphase. This protein is required for stable spindle microtubule capture at kinetochores which is a necessary step in chromosome alignment during prometaphase. This protein also couples chromosome position to microtubule depolymerizing activity. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Nov 2014]

CENPE Gene-Disease associations (from GenCC):

Seckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive primary microcephaly
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
microcephaly 13, primary, autosomal recessive
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina

CENPE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044597983).

BP6

Variant 4-103108928-C-T is Benign according to our data. Variant chr4-103108928-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434698.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001813.3. 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
	CENPE	NM_001813.3	MANE Select	c.7886G>A	p.Arg2629Gln	missense	Exon 48 of 49	NP_001804.2	Q02224-1
	CENPE	NM_001286734.2		c.7523G>A	p.Arg2508Gln	missense	Exon 46 of 47	NP_001273663.1	Q02224-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CENPE	ENST00000265148.9	TSL:2 MANE Select	c.7886G>A	p.Arg2629Gln	missense	Exon 48 of 49	ENSP00000265148.3	Q02224-1
CENPE	ENST00000380026.8	TSL:1	c.7523G>A	p.Arg2508Gln	missense	Exon 46 of 47	ENSP00000369365.3	Q02224-3
CENPE	ENST00000933323.1		c.7889G>A	p.Arg2630Gln	missense	Exon 48 of 49	ENSP00000603382.1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000577

AC:

145

AN:

251232

AF XY:

0.000641

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000328

AC:

479

AN:

1461624

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

278

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33456

American (AMR)

AF:

0.000693

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00146

AC:

126

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000174

AC:

194

AN:

1111848

Other (OTH)

AF:

0.000762

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000276

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41526

American (AMR)

AF:

0.000851

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68002

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000553

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.67

M_CAP

Benign

0.031

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.33

PhyloP100

-1.9

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.24

REVEL

Benign

0.011

Sift

Benign

0.56

Sift4G

Benign

0.92

Polyphen

0.010

Vest4

0.16

MVP

0.39

MPC

0.043

ClinPred

0.014

GERP RS

-3.7

Varity_R

0.015

gMVP

0.075

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over