rs1748892825

Variant names:

• chr4-103106285-A-C
• rs1748892825
• NM_001813.3:c.8043T>G

Your query was ambiguous. Multiple possible variants found:

• chr4-103106285-A-C
• chr4-103106285-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001813.3(CENPE):​c.8043T>G​(p.Asp2681Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2681H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CENPE NM_001813.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.673
• Publications: 0 publications found

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: AR, Unknown Classification: LIMITED Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06643826).

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.8043T>G	p.Asp2681Glu	missense	Exon 49 of 49	NP_001804.2	Q02224-1
	CENPE	NM_001286734.2		c.7680T>G	p.Asp2560Glu	missense	Exon 47 of 47	NP_001273663.1	Q02224-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPE	ENST00000265148.9	TSL:2 MANE Select	c.8043T>G	p.Asp2681Glu	missense	Exon 49 of 49	ENSP00000265148.3	Q02224-1
	CENPE	ENST00000380026.8	TSL:1	c.7680T>G	p.Asp2560Glu	missense	Exon 47 of 47	ENSP00000369365.3	Q02224-3
	CENPE	ENST00000933323.1		c.8046T>G	p.Asp2682Glu	missense	Exon 49 of 49	ENSP00000603382.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449402 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720670

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 43376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39272

South Asian (SAS) AF: 0.00 AC: 0 AN: 83454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105186

Other (OTH) AF: 0.00 AC: 0 AN: 59908

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.16
DANN	Benign	0.94
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.67
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.11
Sift	Benign	0.39	T
Sift4G	Benign	0.89	T
Polyphen		0.010	B
Vest4		0.11
MutPred		0.056		Gain of phosphorylation at S2679 (P = 0.1683)
MVP		0.43
MPC		0.038
ClinPred		0.045	T
GERP RS		-0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.032
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1748892825; hg19: chr4-104027442;