rs35505100

chr4-103146038-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001813.3(CENPE):c.4204A>G(p.Ile1402Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,896 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (43 hom.)
• Consequence: CENPE NM_001813.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.832

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032327771).
• BP6: Variant 4-103146038-T-C is Benign according to our data. Variant chr4-103146038-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 445884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1996/152302) while in subpopulation AFR AF= 0.0427 (1775/41560). AF 95% confidence interval is 0.0411. There are 39 homozygotes in gnomad4. There are 971 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPE	NM_001813.3	c.4204A>G	p.Ile1402Val	missense_variant	30/49	ENST00000265148.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPE	ENST00000265148.9	c.4204A>G	p.Ile1402Val	missense_variant	30/49	2	NM_001813.3	A2
CENPE	ENST00000380026.8	c.4129A>G	p.Ile1377Val	missense_variant	29/47	1		P2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1987 AN: 152184 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00450 AC: 1131 AN: 251250 Hom.: 25 AF XY: 0.00389 AC XY: 528 AN XY: 135822

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00224 AC: 3275 AN: 1461594 Hom.: 43 Cov.: 32 AF XY: 0.00217 AC XY: 1580 AN XY: 727108

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00259

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.000886

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.0131 AC: 1996 AN: 152302 Hom.: 39 Cov.: 32 AF XY: 0.0130 AC XY: 971 AN XY: 74472

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00327 Hom.: 6

Bravo AF: 0.0150

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0404 AC: 178

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00515 AC: 625

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	This variant is associated with the following publications: (PMID: 22974711) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.18
Dann	Benign	0.36
DEOGEN2	Benign	0.035	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.030	N;N;.
REVEL	Benign	0.050
Sift	Benign	0.62	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.028	B;B;.
Vest4		0.11
MVP		0.34
MPC		0.036
ClinPred		0.0035	T
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.027

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: rs35505100; hg19: chr4-104067195;