rs1555298479

Positions:

• chr13-24909868-AATTAGGAGAC-AG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000381884.9(CENPJ):​c.777_786delinsC​(p.Ser260_Asn262del) variant causes a protein altering change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CENPJ ENST00000381884.9 protein_altering
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.34

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000381884.9.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.777_786delinsC	p.Ser260_Asn262del	protein_altering_variant	4/17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.777_786delinsC	p.Ser260_Asn262del	protein_altering_variant	4/17	1	NM_018451.5	ENSP00000371308	P1
CENPJ	ENST00000616936.4	c.777_786delinsC	p.Ser260_Asn262del	protein_altering_variant, NMD_transcript_variant	4/16	1		ENSP00000477511
CENPJ	ENST00000545981.6	c.777_786delinsC	p.Ser260_Asn262del	protein_altering_variant, NMD_transcript_variant	4/18	2		ENSP00000441090

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2023	Not observed in large population cohorts (gnomAD); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 22, 2013

- -

Microcephaly 6, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The deletion insertion c.777_786delGTCTCCTAATinsC (p.Ser260_Asn262del) variant in the CENPJ gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. It has been reported to the ClinVar database as uncertain significance. However no details are available for independent assessment. This variant causes deletion of amino acid Serine at position 260 and of Asparagine at position 262 respectively. For these reasons, this variant has been classified as Uncertain Significance. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555298479; hg19: chr13-25484007;