chr4-103106248-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001813.3(CENPE):c.8080G>A(p.Asp2694Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,596,090 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 3 hom. )

Consequence

CENPE
NM_001813.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.55

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019808501).

BP6

Variant 4-103106248-C-T is Benign according to our data. Variant chr4-103106248-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1216124.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPE	NM_001813.3 link	c.8080G>A	p.Asp2694Asn	missense_variant	Exon 49 of 49	ENST00000265148.9	NP_001804.2	Q02224-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPE	ENST00000265148.9 link	c.8080G>A	p.Asp2694Asn	missense_variant	Exon 49 of 49	2	NM_001813.3	ENSP00000265148.3		Q02224-1
CENPE	ENST00000380026.8 link	c.7717G>A	p.Asp2573Asn	missense_variant	Exon 47 of 47	1		ENSP00000369365.3		Q02224-3

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000694

AC:

169

AN:

243456

Hom.:

AF XY:

0.000814

AC XY:

107

AN XY:

131478

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000245

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00224

GnomAD4 exome

AF:

0.000691

AC:

997

AN:

1443740

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

516

AN XY:

717506

show subpopulations

Gnomad4 AFR exome

AF:

0.000331

Gnomad4 AMR exome

AF:

0.000443

Gnomad4 ASJ exome

AF:

0.000851

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000389

Gnomad4 FIN exome

AF:

0.0000941

Gnomad4 NFE exome

AF:

0.000710

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000643

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000766

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CENPE: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 22, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33337535, 22974711) -

not specified

Uncertain:1

Dec 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CENPE c.8080G>A (p.Asp2694Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 243456 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CENPE causing Microcephaly 13, Primary, Autosomal Recessive, allowing no conclusion about variant significance. c.8080G>A has been reported in the literature in a compound heterozygous individual affected with Type 1 Chiari malformation and as homozugous in a case with unspecified clinical phenotype (Provenzano_2021, Stranneheim_2021). These reports do not provide unequivocal conclusions about association of the variant with Microcephaly 13, Primary, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33337535, 33726816). ClinVar contains an entry for this variant (Variation ID: 1216124). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.85

D;T;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

2.0

M;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

N;N;.

REVEL

Benign

0.13

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;B;.

Vest4

0.18

MVP

0.62

MPC

0.13

ClinPred

0.014

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.13

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over