4-103106248-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (3 hom.)
• Consequence: CENPE NM_001813.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.55

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]

ACMG classification

Verdict is Benign. Variant got -12 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 [Likely_benign]. Clinvar id is 1216124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPE	NM_001813.3	c.8080G>A	p.Asp2694Asn	missense_variant	49/49	ENST00000265148.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPE	ENST00000265148.9	c.8080G>A	p.Asp2694Asn	missense_variant	49/49	2	NM_001813.3	A2
CENPE	ENST00000380026.8	c.7717G>A	p.Asp2573Asn	missense_variant	47/47	1		P2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152232 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000814 AC XY: 107 AN XY: 131478

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.: 3 Cov.: 30 AF XY: 0.000719 AC XY: 516 AN XY: 717506

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: 98 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74496

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.: 1

Bravo AF: 0.000620

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	This variant is associated with the following publications: (PMID: 33337535, 22974711) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CENPE: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.85	D;T;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs61756293; hg19: chr4-104027405;