4-103145116-T-G

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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1597R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0042 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 29 hom. )

Consequence

CENPE
NM_001813.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.06

Publications

5 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=0.0038477182).

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 VariationId is 434695.

BS2

High Homozygotes in GnomAd4 at 5 Unknown,AR 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.4791A>C	p.Arg1597Ser	missense	Exon 32 of 49	NP_001804.2	Q02224-1
	CENPE	NM_001286734.2		c.4716A>C	p.Arg1572Ser	missense	Exon 31 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.4791A>C	p.Arg1597Ser	missense	Exon 32 of 49	ENSP00000265148.3	Q02224-1
CENPE	ENST00000380026.8	TSL:1	c.4716A>C	p.Arg1572Ser	missense	Exon 31 of 47	ENSP00000369365.3	Q02224-3
CENPE	ENST00000933323.1		c.4791A>C	p.Arg1597Ser	missense	Exon 32 of 49	ENSP00000603382.1

Frequencies

GnomAD3 genomes

AF:

0.00424

AC:

645

AN:

152138

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00410

AC:

1024

AN:

249958

AF XY:

0.00443

show subpopulations

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 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.:

Cov.:

AF XY:

0.00539

AC XY:

3914

AN XY:

725716

show subpopulations

African (AFR)

AF:

0.000811

AC:

AN:

33284

American (AMR)

AF:

0.00349

AC:

155

AN:

44386

Ashkenazi Jewish (ASJ)

AF:

0.00265

AC:

AN:

26046

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39616

South Asian (SAS)

AF:

0.000841

AC:

AN:

85590

European-Finnish (FIN)

AF:

0.000921

AC:

AN:

53180

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00648

AC:

7200

AN:

1110802

Other (OTH)

AF:

0.00463

AC:

279

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

388

777

1165

1554

1942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.00423

AC:

644

AN:

152256

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

292

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41566

American (AMR)

AF:

0.00504

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00700

AC:

476

AN:

67996

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00601

Hom.:

Bravo

AF:

0.00465

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00418

AC:

507

Asia WGS

AF:

0.000289

AC:

AN:

3476

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

0.25

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

5.0

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.050

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.1

PhyloP100

-1.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

REVEL

Benign

0.23

Sift

Benign

0.41

Sift4G

Benign

0.094

Polyphen

0.97

Vest4

0.13

MutPred

0.13

Gain of phosphorylation at R1597 (P = 0.0244)

MVP

0.80

MPC

0.043

ClinPred

0.020

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.074

Mutation Taster

=99/1

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