4-103123040-G-C

Variant names:

• chr4-103123040-G-C
• rs61751592
• NM_001813.3:c.6974C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001813.3(CENPE):​c.6974C>G​(p.Ser2325Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,613,702 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (79 hom.)
• Consequence: CENPE NM_001813.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.103
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037833452).
• BP6: Variant 4-103123040-G-C is Benign according to our data. Variant chr4-103123040-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00553 (841/152174) while in subpopulation SAS AF = 0.0185 (89/4810). AF 95% confidence interval is 0.0154. There are 4 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown 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.6974C>G	p.Ser2325Cys	missense	Exon 43 of 49	NP_001804.2	Q02224-1
	CENPE	NM_001286734.2		c.6611C>G	p.Ser2204Cys	missense	Exon 41 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.6974C>G	p.Ser2325Cys	missense	Exon 43 of 49	ENSP00000265148.3	Q02224-1
	CENPE	ENST00000380026.8	TSL:1	c.6611C>G	p.Ser2204Cys	missense	Exon 41 of 47	ENSP00000369365.3	Q02224-3
	CENPE	ENST00000933323.1		c.6977C>G	p.Ser2326Cys	missense	Exon 43 of 49	ENSP00000603382.1

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 841 AN: 152058 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0183

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00743

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00712 AC: 1788 AN: 251248 AF XY: 0.00846

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00691

Gnomad OTH exome AF: 0.00882

GnomAD4 exome AF: 0.00686 AC: 10022 AN: 1461528 Hom.: 79 Cov.: 31 AF XY: 0.00749 AC XY: 5446 AN XY: 727086

African (AFR) AF: 0.00108 AC: 36 AN: 33468

American (AMR) AF: 0.00302 AC: 135 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 499 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39660

South Asian (SAS) AF: 0.0205 AC: 1769 AN: 86244

European-Finnish (FIN) AF: 0.000674 AC: 36 AN: 53396

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5764

European-Non Finnish (NFE) AF: 0.00627 AC: 6976 AN: 1111784

Other (OTH) AF: 0.00803 AC: 485 AN: 60370

GnomAD4 genome AF: 0.00553 AC: 841 AN: 152174 Hom.: 4 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74394

African (AFR) AF: 0.00111 AC: 46 AN: 41522

American (AMR) AF: 0.00550 AC: 84 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4810

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10608

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00743 AC: 505 AN: 67984

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00732 Hom.: 8

Bravo AF: 0.00505

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00713 AC: 865

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	CENPE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.8
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.060	N
PhyloP100		0.10
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.066
Sift	Benign	0.29	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.28
MPC		0.038
ClinPred		0.0025	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.11
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61751592; hg19: chr4-104044197; COSMIC: COSV105020367; COSMIC: COSV105020367;