rs4769388

Variant names:

• chr13-24920996-G-A
• rs4769388
• NM_018451.5:c.-67+1765C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018451.5(CPAP):​c.-67+1765C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 151,822 control chromosomes in the GnomAD database, including 6,617 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6617 hom., cov: 31)
• Consequence: CPAP NM_018451.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAP	NM_018451.5	MANE Select	c.-67+1765C>T		intron	N/A	NP_060921.3
	CPAP	NR_047594.2		n.101+1765C>T		intron	N/A
	CPAP	NR_047595.2		n.101+1765C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAP	ENST00000381884.9	TSL:1 MANE Select	c.-67+1765C>T		intron	N/A	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.-67+1765C>T		intron	N/A	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.-67+1765C>T		intron	N/A	ENSP00000596502.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44151 AN: 151704 Hom.: 6610 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.277

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

GnomAD4 genome AF: 0.291 AC: 44199 AN: 151822 Hom.: 6617 Cov.: 31 AF XY: 0.295 AC XY: 21876 AN XY: 74182

African (AFR) AF: 0.238 AC: 9840 AN: 41356

American (AMR) AF: 0.380 AC: 5791 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1214 AN: 3468

East Asian (EAS) AF: 0.240 AC: 1238 AN: 5154

South Asian (SAS) AF: 0.243 AC: 1168 AN: 4810

European-Finnish (FIN) AF: 0.350 AC: 3672 AN: 10504

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20448 AN: 67962

Other (OTH) AF: 0.275 AC: 581 AN: 2112

Alfa AF: 0.303 Hom.: 5766

Bravo AF: 0.292

Asia WGS AF: 0.215 AC: 748 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.65
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4769388; hg19: chr13-25495134;