rs199422202

Variant names:

• chr13-24913007-AG-A
• rs199422202
• NM_018451.5:c.18delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018451.5(CPAP):​c.18delC​(p.Ser7LeufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CPAP NM_018451.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.625
• Publications: 4 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 67 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-24913007-AG-A is Pathogenic according to our data. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-24913007-AG-A is described in CliVar as Pathogenic. Clinvar id is 1817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAP	NM_018451.5	c.18delC	p.Ser7LeufsTer4	frameshift_variant	Exon 2 of 17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.18delC	p.Ser7LeufsTer4	frameshift_variant	Exon 2 of 17	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000616936.4	n.18delC		non_coding_transcript_exon_variant	Exon 2 of 16	1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.18delC		non_coding_transcript_exon_variant	Exon 2 of 18	2		ENSP00000441090.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249664 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461726 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 6, primary, autosomal recessive Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Microcephaly 1, primary, autosomal recessive Pathogenic:1

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 14, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199422202; hg19: chr13-25487145;