chr4-103145116-T-G

Position:

• chr4-103145116-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001813.3(CENPE):​c.4791A>C​(p.Arg1597Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,611,142 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (29 hom.)
• Consequence: CENPE NM_001813.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.06

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038477182).
• BP6: Variant 4-103145116-T-G is Benign according to our data. Variant chr4-103145116-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434695.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPE	NM_001813.3	c.4791A>C	p.Arg1597Ser	missense_variant	32/49	ENST00000265148.9	NP_001804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPE	ENST00000265148.9	c.4791A>C	p.Arg1597Ser	missense_variant	32/49	2	NM_001813.3	ENSP00000265148	A2
CENPE	ENST00000380026.8	c.4716A>C	p.Arg1572Ser	missense_variant	31/47	1		ENSP00000369365	P2

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 645 AN: 152138 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00410 AC: 1024 AN: 249958 Hom.: 8 AF XY: 0.00443 AC XY: 599 AN XY: 135180

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000855

Gnomad FIN exome AF: 0.000884

Gnomad NFE exome AF: 0.00721

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00539 AC: 7864 AN: 1458886 Hom.: 29 Cov.: 33 AF XY: 0.00539 AC XY: 3914 AN XY: 725716

Gnomad4 AFR exome AF: 0.000811

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.00265

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000841

Gnomad4 FIN exome AF: 0.000921

Gnomad4 NFE exome AF: 0.00648

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00423 AC: 644 AN: 152256 Hom.: 5 Cov.: 32 AF XY: 0.00392 AC XY: 292 AN XY: 74444

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00700

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00617 Hom.: 9

Bravo AF: 0.00465

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00418 AC: 507

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CENPE: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.0
DANN	Benign	0.89
DEOGEN2	Benign	0.050	T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.23
Sift	Benign	0.41	T;T;.
Sift4G	Benign	0.094	T;T;T
Polyphen		0.97	D;D;.
Vest4		0.13
MutPred		0.13		Gain of phosphorylation at R1597 (P = 0.0244);.;Gain of phosphorylation at R1597 (P = 0.0244);
MVP		0.80
MPC		0.043
ClinPred		0.020	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.074

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: rs61751594; hg19: chr4-104066273;