chr13-24909869-ATTAGGAGAC-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM4 BP7

The NM_018451.5(CPAP):​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 (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPAP NM_018451.5 disruptive_inframe_deletion, synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.34
• Publications: 0 publications found

Genes affected

CPAP (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]

CPAP Gene-Disease associations (from GenCC):

• microcephaly 6 with or without short stature

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• microcephaly 6, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018451.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAP	NM_018451.5	MANE Select	c.777_786delGTCTCCTAATinsC	p.Ser260_Asn262del	disruptive_inframe_deletion synonymous	Exon 4 of 17	NP_060921.3
	CPAP	NR_047594.2		n.944_953delGTCTCCTAATinsC		non_coding_transcript_exon	Exon 4 of 18
	CPAP	NR_047595.2		n.944_953delGTCTCCTAATinsC		non_coding_transcript_exon	Exon 4 of 16

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPJ	ENST00000381884.9	TSL:1 MANE Select	c.777_786delGTCTCCTAATinsC	p.Ser260_Asn262del	disruptive_inframe_deletion synonymous	Exon 4 of 17	ENSP00000371308.4
	CENPJ	ENST00000616936.4	TSL:1	n.777_786delGTCTCCTAATinsC		non_coding_transcript_exon	Exon 4 of 16	ENSP00000477511.1
	CENPJ	ENST00000545981.6	TSL:2	n.777_786delGTCTCCTAATinsC		non_coding_transcript_exon	Exon 4 of 18	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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Microcephaly 6, primary, autosomal recessive (1)
-	1	-	Microcephaly 6, primary, autosomal recessive;C3888212:Seckel syndrome 4 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3

Splicing

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

Other links and lift over

dbSNP: rs1555298479; hg19: chr13-25484007;