rs749343808

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018451.5(CENPJ):c.2872C>T(p.Arg958*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000013 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CENPJ
NM_018451.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.12

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-24899538-G-A is Pathogenic according to our data. Variant chr13-24899538-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPJ	NM_018451.5 link	c.2872C>T	p.Arg958*	stop_gained	Exon 9 of 17	ENST00000381884.9	NP_060921.3	Q9HC77-1A8K8P1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CENPJ	ENST00000381884.9 link	c.2872C>T	p.Arg958*	stop_gained	Exon 9 of 17	1	NM_018451.5	ENSP00000371308.4	Q9HC77-1
CENPJ	ENST00000418179.1 link	c.115C>T	p.Arg39*	stop_gained	Exon 2 of 4	1		ENSP00000399334.1	H0Y5L8
CENPJ	ENST00000616936.4 link	n.2872C>T		non_coding_transcript_exon_variant	Exon 9 of 16	1		ENSP00000477511.1	Q9HC77-2
CENPJ	ENST00000545981.6 link	n.2872C>T		non_coding_transcript_exon_variant	Exon 9 of 18	2		ENSP00000441090.2	F6VUX8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251022

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Apr 20, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R958X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R958X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, it was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this variant has not been reported previously to our knowledge, another truncating variant downstream of this position has been reported in the Human Gene Mutation Database in association with a CENPJ-related disorder (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. GeneDx interprets R958X as a likely pathogenic variant. -

May 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs749343808, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg958*) in the CENPJ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CENPJ are known to be pathogenic (PMID: 15793586, 16900296, 20522431). This variant has not been reported in the literature in individuals affected with CENPJ-related conditions. ClinVar contains an entry for this variant (Variation ID: 432139). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.89

Vest4

0.88

ClinPred

1.0

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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