rs35498994

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018451.5(CENPJ):c.61A>T(p.Met21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00465 in 1,614,092 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M21V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0053 ( 22 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 238 hom. )

Consequence

CENPJ
NM_018451.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.65

Variant links:

Genes affected

CENPJ (HGNC:17272): (centromere protein J) This gene encodes a protein that belongs to the centromere protein family. During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway, and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein. Mutations in this gene are associated with primary autosomal recessive microcephaly, a disorder characterized by severely reduced brain size and cognitive disability. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2012]

CENPJ links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031332672).

BP6

Variant 13-24912965-T-A is Benign according to our data. Variant chr13-24912965-T-A is described in ClinVar as [Benign]. Clinvar id is 158217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24912965-T-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5 linkuse as main transcript	c.61A>T	p.Met21Leu	missense_variant	2/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9 linkuse as main transcript	c.61A>T	p.Met21Leu	missense_variant	2/17	1	NM_018451.5	P1	Q9HC77-1
CENPJ	ENST00000616936.4 linkuse as main transcript	c.61A>T	p.Met21Leu	missense_variant, NMD_transcript_variant	2/16	1			Q9HC77-2
CENPJ	ENST00000545981.6 linkuse as main transcript	c.61A>T	p.Met21Leu	missense_variant, NMD_transcript_variant	2/18	2

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

805

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0806

Gnomad SAS

AF:

0.00496

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00815

GnomAD3 exomes

AF:

0.0115

AC:

2880

AN:

250918

Hom.:

AF XY:

0.0100

AC XY:

1357

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.0276

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0867

Gnomad SAS exome

AF:

0.00229

Gnomad FIN exome

AF:

0.00458

Gnomad NFE exome

AF:

0.000821

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00458

AC:

6698

AN:

1461850

Hom.:

238

Cov.:

AF XY:

0.00439

AC XY:

3192

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.0257

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.104

Gnomad4 SAS exome

AF:

0.00297

Gnomad4 FIN exome

AF:

0.00530

Gnomad4 NFE exome

AF:

0.000450

Gnomad4 OTH exome

AF:

0.00561

GnomAD4 genome

AF:

0.00530

AC:

807

AN:

152242

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

452

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0806

Gnomad4 SAS

AF:

0.00517

Gnomad4 FIN

AF:

0.00368

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00759

Alfa

AF:

0.000262

Hom.:

1138

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0106

AC:

1285

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Seckel syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Microcephaly 6, primary, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

0.92

N;N

PrimateAI

Uncertain

0.49

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.65

.;P;.

Vest4

0.36

MutPred

0.28

Gain of catalytic residue at P24 (P = 0.0102);Gain of catalytic residue at P24 (P = 0.0102);Gain of catalytic residue at P24 (P = 0.0102);

MPC

0.11

ClinPred

0.065

GERP RS

5.3

Varity_R

0.79

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over