rs116981543

Positions:

chr13-24912958-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.68A>G(p.Asn23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,208 control chromosomes in the GnomAD database, including 73 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 0.0031 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 65 hom. )

Consequence

CENPJ
NM_018451.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0280

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=0.0038710237).

BP6

Variant 13-24912958-T-C is Benign according to our data. Variant chr13-24912958-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24912958-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00314 (478/152334) while in subpopulation EAS AF= 0.0237 (123/5182). AF 95% confidence interval is 0.0203. There are 8 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5 linkuse as main transcript	c.68A>G	p.Asn23Ser	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.68A>G	p.Asn23Ser	missense_variant	2/17	1	NM_018451.5	P1	Q9HC77-1
CENPJ	ENST00000616936.4 linkuse as main transcript	c.68A>G	p.Asn23Ser	missense_variant, NMD_transcript_variant	2/16	1			Q9HC77-2
CENPJ	ENST00000545981.6 linkuse as main transcript	c.68A>G	p.Asn23Ser	missense_variant, NMD_transcript_variant	2/18	2

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

474

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0237

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00674

AC:

1692

AN:

251084

Hom.:

AF XY:

0.00552

AC XY:

749

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.0277

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0242

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00458

Gnomad NFE exome

AF:

0.000767

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00266

AC:

3886

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1828

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.0258

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.0425

Gnomad4 SAS exome

AF:

0.00184

Gnomad4 FIN exome

AF:

0.00530

Gnomad4 NFE exome

AF:

0.000383

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00314

AC:

478

AN:

152334

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

271

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0237

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00367

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000948

Hom.:

Bravo

AF:

0.00436

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00604

AC:

733

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

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	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephaly 6, primary, autosomal recessive;C3888212:Seckel syndrome 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

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

0.059

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.4

DANN

Benign

0.80

DEOGEN2

Benign

0.0075

.;T;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.71

T;T;T

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.58

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.068

Sift

Benign

0.49

.;T;T

Sift4G

Benign

0.66

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.14

MVP

0.19

MPC

0.098

ClinPred

0.0013

GERP RS

-2.7

Varity_R

0.021

gMVP

0.094

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