13-24892636-T-C

Position:

• chr13-24892636-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018451.5(CENPJ):​c.3216+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 1,611,198 control chromosomes in the GnomAD database, including 538,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46483 hom., cov: 29)
  • Exomes 𝑓: 0.82 (491891 hom.)
• Consequence: CENPJ NM_018451.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002216
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.975

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-24892636-T-C is Benign according to our data. Variant chr13-24892636-T-C is described in ClinVar as [Benign]. Clinvar id is 158208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24892636-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.3216+7A>G		splice_region_variant, intron_variant		ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.3216+7A>G		splice_region_variant, intron_variant		1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000418179.1	c.459+7A>G		splice_region_variant, intron_variant		1		ENSP00000399334.1
CENPJ	ENST00000616936.4	n.3216+7A>G		splice_region_variant, intron_variant		1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.3216+7A>G		splice_region_variant, intron_variant		2		ENSP00000441090.2

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118044 AN: 151832 Hom.: 46453 Cov.: 29

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.772

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.767

GnomAD3 exomes AF: 0.808 AC: 203202 AN: 251418 Hom.: 82949 AF XY: 0.801 AC XY: 108889 AN XY: 135900

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.880

Gnomad ASJ exome AF: 0.762

Gnomad EAS exome AF: 0.845

Gnomad SAS exome AF: 0.672

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.828

Gnomad OTH exome AF: 0.814

GnomAD4 exome AF: 0.819 AC: 1195413 AN: 1459248 Hom.: 491891 Cov.: 36 AF XY: 0.815 AC XY: 591576 AN XY: 726116

Gnomad4 AFR exome AF: 0.646

Gnomad4 AMR exome AF: 0.873

Gnomad4 ASJ exome AF: 0.761

Gnomad4 EAS exome AF: 0.864

Gnomad4 SAS exome AF: 0.677

Gnomad4 FIN exome AF: 0.893

Gnomad4 NFE exome AF: 0.831

Gnomad4 OTH exome AF: 0.798

GnomAD4 genome AF: 0.777 AC: 118120 AN: 151950 Hom.: 46483 Cov.: 29 AF XY: 0.778 AC XY: 57782 AN XY: 74268

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.820

Gnomad4 ASJ AF: 0.772

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.665

Gnomad4 FIN AF: 0.888

Gnomad4 NFE AF: 0.828

Gnomad4 OTH AF: 0.759

Alfa AF: 0.808 Hom.: 31121

Bravo AF: 0.770

Asia WGS AF: 0.725 AC: 2520 AN: 3478

EpiCase AF: 0.813

EpiControl AF: 0.815

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
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 09, 2014	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Seckel syndrome 4 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Microcephaly 6, primary, autosomal recessive Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.088
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs9318917; hg19: chr13-25466774;