NM_018451.5:c.3216+7A>G

Variant names:

• chr13-24892636-T-C
• rs9318917
• NM_018451.5:c.3216+7A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018451.5(CPAP):​c.3216+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 1,611,198 control chromosomes in the GnomAD database, including 538,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46483 hom., cov: 29)
  • Exomes 𝑓: 0.82 (491891 hom.)
• Consequence: CPAP NM_018451.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002216
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.975
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-24892636-T-C is Benign according to our data. Variant chr13-24892636-T-C is described in ClinVar as Benign. ClinVar VariationId is 158208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

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.3216+7A>G		splice_region intron	N/A	NP_060921.3
	CPAP	NR_047594.2		n.3383+7A>G		splice_region intron	N/A
	CPAP	NR_047595.2		n.3383+7A>G		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPJ	ENST00000381884.9	TSL:1 MANE Select	c.3216+7A>G		splice_region intron	N/A	ENSP00000371308.4
	CENPJ	ENST00000418179.1	TSL:1	c.459+7A>G		splice_region intron	N/A	ENSP00000399334.1
	CENPJ	ENST00000616936.4	TSL:1	n.3216+7A>G		splice_region intron	N/A	ENSP00000477511.1

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118044 AN: 151832 Hom.: 46453 Cov.: 29

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.772

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.767

GnomAD2 exomes AF: 0.808 AC: 203202 AN: 251418 AF XY: 0.801

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.880

Gnomad ASJ exome AF: 0.762

Gnomad EAS exome AF: 0.845

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.828

Gnomad OTH exome AF: 0.814

GnomAD4 exome AF: 0.819 AC: 1195413 AN: 1459248 Hom.: 491891 Cov.: 36 AF XY: 0.815 AC XY: 591576 AN XY: 726116

African (AFR) AF: 0.646 AC: 21589 AN: 33398

American (AMR) AF: 0.873 AC: 39019 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 19883 AN: 26122

East Asian (EAS) AF: 0.864 AC: 34307 AN: 39690

South Asian (SAS) AF: 0.677 AC: 58355 AN: 86186

European-Finnish (FIN) AF: 0.893 AC: 47622 AN: 53350

Middle Eastern (MID) AF: 0.751 AC: 4191 AN: 5580

European-Non Finnish (NFE) AF: 0.831 AC: 922341 AN: 1109912

Other (OTH) AF: 0.798 AC: 48106 AN: 60290

GnomAD4 genome AF: 0.777 AC: 118120 AN: 151950 Hom.: 46483 Cov.: 29 AF XY: 0.778 AC XY: 57782 AN XY: 74268

African (AFR) AF: 0.655 AC: 27092 AN: 41372

American (AMR) AF: 0.820 AC: 12522 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 2676 AN: 3468

East Asian (EAS) AF: 0.852 AC: 4414 AN: 5180

South Asian (SAS) AF: 0.665 AC: 3188 AN: 4794

European-Finnish (FIN) AF: 0.888 AC: 9378 AN: 10564

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56311 AN: 67984

Other (OTH) AF: 0.759 AC: 1603 AN: 2112

Alfa AF: 0.805 Hom.: 34950

Bravo AF: 0.770

Asia WGS AF: 0.725 AC: 2520 AN: 3478

EpiCase AF: 0.813

EpiControl AF: 0.815

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Seckel syndrome 4 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.088
DANN	Benign	0.32
PhyloP100		-0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.040		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: rs9318917; hg19: chr13-25466774;