13-24892817-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018451.5(CENPJ):c.3042A>G(p.Glu1014=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,610,908 control chromosomes in the GnomAD database, including 236,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18933 hom., cov: 29)
  • Exomes 𝑓: 0.54 (217968 hom.)
• Consequence: CENPJ NM_018451.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.210

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 13-24892817-T-C is Benign according to our data. Variant chr13-24892817-T-C is described in ClinVar as [Benign]. Clinvar id is 158207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24892817-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.3042A>G	p.Glu1014=	synonymous_variant	10/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.3042A>G	p.Glu1014=	synonymous_variant	10/17	1	NM_018451.5	P1
CENPJ	ENST00000418179.1	c.288A>G	p.Glu96=	synonymous_variant	3/4	1
CENPJ	ENST00000616936.4	c.3042A>G	p.Glu1014=	synonymous_variant, NMD_transcript_variant	10/16	1
CENPJ	ENST00000545981.6	c.3042A>G	p.Glu1014=	synonymous_variant, NMD_transcript_variant	10/18	2

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73107 AN: 151358 Hom.: 18914 Cov.: 29

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.485

GnomAD3 exomes AF: 0.549 AC: 137988 AN: 251456 Hom.: 39117 AF XY: 0.544 AC XY: 73993 AN XY: 135906

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.649

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.712

Gnomad SAS exome AF: 0.496

Gnomad FIN exome AF: 0.625

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.543 AC: 792195 AN: 1459432 Hom.: 217968 Cov.: 44 AF XY: 0.541 AC XY: 393000 AN XY: 726172

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.639

Gnomad4 ASJ exome AF: 0.501

Gnomad4 EAS exome AF: 0.712

Gnomad4 SAS exome AF: 0.496

Gnomad4 FIN exome AF: 0.618

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.529

GnomAD4 genome AF: 0.483 AC: 73158 AN: 151476 Hom.: 18933 Cov.: 29 AF XY: 0.490 AC XY: 36199 AN XY: 73950

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.490

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.534

Gnomad4 OTH AF: 0.482

Alfa AF: 0.508 Hom.: 24821

Bravo AF: 0.473

Asia WGS AF: 0.559 AC: 1937 AN: 3476

EpiCase AF: 0.520

EpiControl AF: 0.528

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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)	Jul 28, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Seckel syndrome 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	9.0
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs3742165; hg19: chr13-25466955; COSMIC: COSV67883227; COSMIC: COSV67883227;