NM_018451.5:c.133C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_018451.5(CPAP):c.133C>T(p.Arg45*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CPAP
NM_018451.5 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.70

Publications

2 publications found

Variant links:

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

CPAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-24912893-G-A is Pathogenic according to our data. Variant chr13-24912893-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191040.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAP	NM_018451.5 link	c.133C>T	p.Arg45*	stop_gained	Exon 2 of 17	ENST00000381884.9	NP_060921.3	Q9HC77-1A8K8P1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CENPJ	ENST00000381884.9 link	c.133C>T	p.Arg45*	stop_gained	Exon 2 of 17	1	NM_018451.5	ENSP00000371308.4	Q9HC77-1
CENPJ	ENST00000616936.4 link	n.133C>T		non_coding_transcript_exon_variant	Exon 2 of 16	1		ENSP00000477511.1	Q9HC77-2
CENPJ	ENST00000545981.6 link	n.133C>T		non_coding_transcript_exon_variant	Exon 2 of 18	2		ENSP00000441090.2	F6VUX8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152128

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251344

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Alfa

AF:

0.0000141

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.028

FATHMM_MKL

Benign

0.44

PhyloP100

2.7

Vest4

0.47

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over