rs2290277

Variant names:

• chr13-24912236-C-T
• rs2290277
• NM_018451.5:c.445-167G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018451.5(CPAP):​c.445-167G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,076 control chromosomes in the GnomAD database, including 1,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1587 hom., cov: 32)
• Consequence: CPAP NM_018451.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.448
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-24912236-C-T is Benign according to our data. Variant chr13-24912236-C-T is described in ClinVar as Benign. ClinVar VariationId is 1286855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAP	NM_018451.5	c.445-167G>A		intron_variant	Intron 2 of 16	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.445-167G>A		intron_variant	Intron 2 of 16	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000616936.4	n.445-167G>A		intron_variant	Intron 2 of 15	1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.445-167G>A		intron_variant	Intron 2 of 17	2		ENSP00000441090.2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20607 AN: 151958 Hom.: 1584 Cov.: 32

Gnomad AFR AF: 0.0989

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.0931

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.134

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

GnomAD4 genome AF: 0.136 AC: 20618 AN: 152076 Hom.: 1587 Cov.: 32 AF XY: 0.137 AC XY: 10158 AN XY: 74348

African (AFR) AF: 0.0989 AC: 4103 AN: 41494

American (AMR) AF: 0.151 AC: 2303 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.317 AC: 1641 AN: 5170

South Asian (SAS) AF: 0.0938 AC: 452 AN: 4818

European-Finnish (FIN) AF: 0.192 AC: 2032 AN: 10560

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9552 AN: 67980

Other (OTH) AF: 0.133 AC: 280 AN: 2106

Alfa AF: 0.135 Hom.: 1221

Bravo AF: 0.135

Asia WGS AF: 0.189 AC: 655 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.8
DANN	Benign	0.70
PhyloP100		0.45
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: rs2290277; hg19: chr13-25486374;