rs75985315

chr13-24906157-C-T

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.1881G>A(p.Pro627=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,606 control chromosomes in the GnomAD database, including 1,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (199 hom., cov: 33)
  • Exomes 𝑓: 0.010 (1264 hom.)
• Consequence: CENPJ NM_018451.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.98

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=-0.85).
• BP6: Variant 13-24906157-C-T is Benign according to our data. Variant chr13-24906157-C-T is described in ClinVar as [Benign]. Clinvar id is 95909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24906157-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPJ	NM_018451.5	c.1881G>A	p.Pro627=	synonymous_variant	7/17	ENST00000381884.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPJ	ENST00000381884.9	c.1881G>A	p.Pro627=	synonymous_variant	7/17	1	NM_018451.5	P1
CENPJ	ENST00000616936.4	c.1881G>A	p.Pro627=	synonymous_variant, NMD_transcript_variant	7/16	1
CENPJ	ENST00000545981.6	c.1881G>A	p.Pro627=	synonymous_variant, NMD_transcript_variant	7/18	2

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2748 AN: 152080 Hom.: 194 Cov.: 33

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.0864

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0371 AC: 9325 AN: 251226 Hom.: 951 AF XY: 0.0291 AC XY: 3948 AN XY: 135770

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.0774

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000792

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0100 AC: 14645 AN: 1461408 Hom.: 1264 Cov.: 34 AF XY: 0.00897 AC XY: 6517 AN XY: 726900

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.00919

Gnomad4 EAS exome AF: 0.0968

Gnomad4 SAS exome AF: 0.00316

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0181 AC: 2761 AN: 152198 Hom.: 199 Cov.: 33 AF XY: 0.0217 AC XY: 1614 AN XY: 74412

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.0865

Gnomad4 SAS AF: 0.00602

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00521 Hom.: 18

Bravo AF: 0.0277

Asia WGS AF: 0.0420 AC: 145 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

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:1

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. -

Microcephaly 6, primary, autosomal recessive Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.46
Dann	Benign	0.35

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: rs75985315; hg19: chr13-25480295; COSMIC: COSV67882944; COSMIC: COSV67882944;