4-103148938-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001813.3(CENPE):c.3749C>G(p.Thr1250Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,502 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CENPE NM_001813.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.80

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063459277).
• BP6: Variant 4-103148938-G-C is Benign according to our data. Variant chr4-103148938-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434696.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPE	NM_001813.3	c.3749C>G	p.Thr1250Ser	missense_variant	28/49	ENST00000265148.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPE	ENST00000265148.9	c.3749C>G	p.Thr1250Ser	missense_variant	28/49	2	NM_001813.3	A2
CENPE	ENST00000380026.8	c.3674C>G	p.Thr1225Ser	missense_variant	27/47	1		P2

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000577 AC: 145 AN: 251224 Hom.: 0 AF XY: 0.000398 AC XY: 54 AN XY: 135778

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000229 AC: 335 AN: 1461258 Hom.: 0 Cov.: 31 AF XY: 0.000184 AC XY: 134 AN XY: 726952

Gnomad4 AFR exome AF: 0.00858

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74464

Gnomad4 AFR AF: 0.00717

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000789 Hom.: 0

Bravo AF: 0.00209

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000651 AC: 79

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 16, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

CENPE-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.074	T;.;.
Eigen	Benign	0.057
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.93	N;N;.
REVEL	Benign	0.15
Sift	Uncertain	0.026	D;T;.
Sift4G	Benign	0.70	T;T;T
Polyphen		0.97	D;P;.
Vest4		0.28
MutPred		0.11		Gain of phosphorylation at T1250 (P = 0.0682);.;Gain of phosphorylation at T1250 (P = 0.0682);
MVP		0.64
MPC		0.053
ClinPred		0.020	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.056

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: rs114698062; hg19: chr4-104070095; COSMIC: COSV99035773; COSMIC: COSV99035773;