rs61739263

Positions:

chr13-24912739-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018451.5(CENPJ):c.287A>G(p.His96Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,614,202 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 30 hom. )

Consequence

CENPJ
NM_018451.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.02

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:

CENPJ (HGNC:):

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=0.0024003983).

BP6

Variant 13-24912739-T-C is Benign according to our data. Variant chr13-24912739-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24912739-T-C is described in Lovd as [Benign]. Variant chr13-24912739-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1701/152312) while in subpopulation AFR AF= 0.0372 (1544/41550). AF 95% confidence interval is 0.0356. There are 40 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5 linkuse as main transcript	c.287A>G	p.His96Arg	missense_variant	2/17	ENST00000381884.9	NP_060921.3	Q9HC77-1A8K8P1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CENPJ	ENST00000381884.9 linkuse as main transcript	c.287A>G	p.His96Arg	missense_variant	2/17	1	NM_018451.5	ENSP00000371308.4	Q9HC77-1
CENPJ	ENST00000616936.4 linkuse as main transcript	n.287A>G		non_coding_transcript_exon_variant	2/16	1		ENSP00000477511.1	Q9HC77-2
CENPJ	ENST00000545981.6 linkuse as main transcript	n.287A>G		non_coding_transcript_exon_variant	2/18	2		ENSP00000441090.2	F6VUX8

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1700

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0372

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.00337

AC:

847

AN:

251490

Hom.:

AF XY:

0.00249

AC XY:

338

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0395

Gnomad AMR exome

AF:

0.00373

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000492

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00137

AC:

2001

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

849

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0379

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000270

Gnomad4 OTH exome

AF:

0.00316

GnomAD4 genome

AF:

0.0112

AC:

1701

AN:

152312

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

820

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0372

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00226

Hom.:

Bravo

AF:

0.0130

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0445

AC:

196

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00400

AC:

485

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 26, 2013	- -

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

CENPJ-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.14

DANN

Benign

0.54

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.57

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

.;N;N

REVEL

Benign

0.036

Sift

Benign

0.76

.;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.0060

.;B;.

Vest4

0.061

MVP

0.35

MPC

0.15

ClinPred

0.0028

GERP RS

-1.2

Varity_R

0.020

gMVP

0.064

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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