rs61729909

Positions:

• chr13-24906007-G-A

Variant summary

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

The ENST00000381884.9(CENPJ):​c.2031C>T​(p.Ala677=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,614,032 control chromosomes in the GnomAD database, including 336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (271 hom.)
• Consequence: CENPJ ENST00000381884.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.741

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=-0.76).
• BP6: Variant 13-24906007-G-A is Benign according to our data. Variant chr13-24906007-G-A is described in ClinVar as [Benign]. Clinvar id is 158199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24906007-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.741 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.2031C>T	p.Ala677=	synonymous_variant	7/17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.2031C>T	p.Ala677=	synonymous_variant	7/17	1	NM_018451.5	ENSP00000371308	P1
CENPJ	ENST00000616936.4	c.2031C>T	p.Ala677=	synonymous_variant, NMD_transcript_variant	7/16	1		ENSP00000477511
CENPJ	ENST00000545981.6	c.2031C>T	p.Ala677=	synonymous_variant, NMD_transcript_variant	7/18	2		ENSP00000441090

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2502 AN: 152072 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0791

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.0197

GnomAD3 exomes AF: 0.0147 AC: 3696 AN: 251250 Hom.: 101 AF XY: 0.0124 AC XY: 1680 AN XY: 135804

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0850

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00458

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.00590 AC: 8621 AN: 1461842 Hom.: 271 Cov.: 34 AF XY: 0.00549 AC XY: 3995 AN XY: 727228

Gnomad4 AFR exome AF: 0.0386

Gnomad4 AMR exome AF: 0.0296

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.00307

Gnomad4 FIN exome AF: 0.00530

Gnomad4 NFE exome AF: 0.000725

Gnomad4 OTH exome AF: 0.00861

GnomAD4 genome AF: 0.0165 AC: 2505 AN: 152190 Hom.: 65 Cov.: 33 AF XY: 0.0171 AC XY: 1270 AN XY: 74406

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0791

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.00676 Hom.: 7

Bravo AF: 0.0200

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	- -

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 28, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Seckel syndrome 4 Benign:1

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:1

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	-0.76
CADD	Benign	3.9
DANN	Benign	0.46

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: rs61729909; hg19: chr13-25480145; COSMIC: COSV67883104; COSMIC: COSV67883104;