rs112133852

chr13-24906805-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_018451.5(CENPJ):c.1233G>A(p.Pro411=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,614,166 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: CENPJ NM_018451.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.426

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-24906805-C-T is Benign according to our data. Variant chr13-24906805-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24906805-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00341 (519/152278) while in subpopulation AFR AF= 0.0118 (490/41564). AF 95% confidence interval is 0.0109. There are 1 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.1233G>A	p.Pro411=	synonymous_variant	7/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.1233G>A	p.Pro411=	synonymous_variant	7/17	1	NM_018451.5	P1
CENPJ	ENST00000616936.4	c.1233G>A	p.Pro411=	synonymous_variant, NMD_transcript_variant	7/16	1
CENPJ	ENST00000545981.6	c.1233G>A	p.Pro411=	synonymous_variant, NMD_transcript_variant	7/18	2

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000959 AC: 241 AN: 251372 Hom.: 0 AF XY: 0.000780 AC XY: 106 AN XY: 135866

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000376

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: 0.0000792

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000430 AC: 628 AN: 1461888 Hom.: 5 Cov.: 34 AF XY: 0.000380 AC XY: 276 AN XY: 727244

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.00314 AC XY: 234 AN XY: 74460

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.00359

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CENPJ: BP4, BP7, BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

CENPJ-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.71
Dann	Benign	0.25

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: rs112133852; hg19: chr13-25480943;