4-103146038-T-C

Variant names:

• chr4-103146038-T-C
• rs35505100
• NM_001813.3:c.4204A>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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (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:4
• Conservation: PhyloP100: -0.832
• Publications: 7 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.4204A>G	p.Ile1402Val	missense	Exon 30 of 49	NP_001804.2
	CENPE	NM_001286734.2		c.4129A>G	p.Ile1377Val	missense	Exon 29 of 47	NP_001273663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPE	ENST00000265148.9	TSL:2 MANE Select	c.4204A>G	p.Ile1402Val	missense	Exon 30 of 49	ENSP00000265148.3
	CENPE	ENST00000380026.8	TSL:1	c.4129A>G	p.Ile1377Val	missense	Exon 29 of 47	ENSP00000369365.3
	CENPE	ENST00000933323.1		c.4204A>G	p.Ile1402Val	missense	Exon 30 of 49	ENSP00000603382.1

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

GnomAD2 exomes AF: 0.00450 AC: 1131 AN: 251250 AF XY: 0.00389

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 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

African (AFR) AF: 0.0454 AC: 1519 AN: 33462

American (AMR) AF: 0.00465 AC: 208 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00259 AC: 223 AN: 86248

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53384

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5764

European-Non Finnish (NFE) AF: 0.000886 AC: 985 AN: 1111864

Other (OTH) AF: 0.00419 AC: 253 AN: 60382

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

African (AFR) AF: 0.0427 AC: 1775 AN: 41560

American (AMR) AF: 0.00699 AC: 107 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68016

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00392 Hom.: 8

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.83
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.050
Sift	Benign	0.62	T
Sift4G	Benign	1.0	T
Polyphen		0.028	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs35505100; hg19: chr4-104067195;