rs1555298479

Variant names:

• chr13-24909869-ATTAGGAGAC-G
• rs1555298479
• NM_018451.5:c.777_786delGTCTCCTAATinsC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4 BP7

The NM_018451.5(CENPJ):​c.777_786delGTCTCCTAATinsC​(p.Ser260_Asn262del) variant causes a disruptive inframe deletion, synonymous 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CENPJ NM_018451.5 disruptive_inframe_deletion, synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_018451.5.
• BP7: Synonymous conserved (PhyloP=2.34 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPJ	NM_018451.5	c.777_786delGTCTCCTAATinsC	p.Ser260_Asn262del	disruptive_inframe_deletion, synonymous_variant	Exon 4 of 17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.777_786delGTCTCCTAATinsC	p.Ser260_Asn262del	disruptive_inframe_deletion, synonymous_variant	Exon 4 of 17	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000616936.4	n.777_786delGTCTCCTAATinsC		non_coding_transcript_exon_variant	Exon 4 of 16	1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.777_786delGTCTCCTAATinsC		non_coding_transcript_exon_variant	Exon 4 of 18	2		ENSP00000441090.2

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Aug 23, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Microcephaly 6, primary, autosomal recessive;C3888212:Seckel syndrome 4 Uncertain:1

Mar 02, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Uncertain:1

Aug 22, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly 6, primary, autosomal recessive Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;