13-24912965-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018451.5(CPAP):c.61A>G(p.Met21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,936 control chromosomes in the GnomAD database, including 17,819 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M21L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.14 ( 1599 hom., cov: 32)

Exomes 𝑓: 0.14 ( 16220 hom. )

Consequence

CPAP
NM_018451.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 2.65

Publications

27 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048995316).

BP6

Variant 13-24912965-T-C is Benign according to our data. Variant chr13-24912965-T-C is described in ClinVar as Benign. ClinVar VariationId is 21666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAP	NM_018451.5 link	c.61A>G	p.Met21Val	missense_variant	Exon 2 of 17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CENPJ	ENST00000381884.9 link	c.61A>G	p.Met21Val	missense_variant	Exon 2 of 17	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000616936.4 link	n.61A>G		non_coding_transcript_exon_variant	Exon 2 of 16	1		ENSP00000477511.1
CENPJ	ENST00000545981.6 link	n.61A>G		non_coding_transcript_exon_variant	Exon 2 of 18	2		ENSP00000441090.2

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20655

AN:

152102

Hom.:

1596

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0989

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.320

Gnomad SAS

AF:

0.0928

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.133

GnomAD2 exomes

AF:

0.149

AC:

37299

AN:

250918

AF XY:

0.143

show subpopulations

Gnomad AFR exome

AF:

0.0978

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.0454

Gnomad EAS exome

AF:

0.334

Gnomad FIN exome

AF:

0.202

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.144

AC:

211011

AN:

1461716

Hom.:

16220

Cov.:

AF XY:

0.141

AC XY:

102833

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0939

AC:

3145

AN:

33478

American (AMR)

AF:

0.162

AC:

7260

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0473

AC:

1235

AN:

26134

East Asian (EAS)

AF:

0.275

AC:

10932

AN:

39694

South Asian (SAS)

AF:

0.0820

AC:

7072

AN:

86252

European-Finnish (FIN)

AF:

0.202

AC:

10812

AN:

53406

Middle Eastern (MID)

AF:

0.0560

AC:

323

AN:

5768

European-Non Finnish (NFE)

AF:

0.145

AC:

161396

AN:

1111870

Other (OTH)

AF:

0.146

AC:

8836

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

9941

19882

29823

39764

49705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5896

11792

17688

23584

29480

<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

AF:

0.136

AC:

20666

AN:

152220

Hom.:

1599

Cov.:

AF XY:

0.137

AC XY:

10194

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0989

AC:

4107

AN:

41544

American (AMR)

AF:

0.151

AC:

2308

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0418

AC:

145

AN:

3470

East Asian (EAS)

AF:

0.319

AC:

1653

AN:

5178

South Asian (SAS)

AF:

0.0935

AC:

452

AN:

4832

European-Finnish (FIN)

AF:

0.193

AC:

2047

AN:

10584

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9566

AN:

68004

Other (OTH)

AF:

0.132

AC:

278

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

912

1825

2737

3650

4562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

226

452

678

904

1130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.129

Hom.:

2121

Bravo

AF:

0.137

TwinsUK

AF:

0.148

AC:

547

ALSPAC

AF:

0.135

AC:

522

ESP6500AA

AF:

0.0958

AC:

422

ESP6500EA

AF:

0.135

AC:

1162

ExAC

AF:

0.144

AC:

17507

EpiCase

AF:

0.130

EpiControl

AF:

0.132

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Dec 18, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Microcephaly 6, primary, autosomal recessive

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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. -

Seckel syndrome 4

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Seckel syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

.;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.60

T;T;T

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.7

M;M;.

PhyloP100

2.7

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

.;N;N

REVEL

Benign

0.14

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;T;D

Polyphen

0.81

.;P;.

Vest4

0.29

MPC

0.12

ClinPred

0.065

GERP RS

5.3

Varity_R

0.77

gMVP

0.63

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over