13-24892817-T-G

Variant names:

• chr13-24892817-T-G
• rs3742165
• NM_018451.5:c.3042A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018451.5(CPAP):​c.3042A>C​(p.Glu1014Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1014E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210
• Publications: 19 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAP	NM_018451.5	c.3042A>C	p.Glu1014Asp	missense_variant	Exon 10 of 17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.3042A>C	p.Glu1014Asp	missense_variant	Exon 10 of 17	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000418179.1	c.285A>C	p.Glu95Asp	missense_variant	Exon 3 of 4	1		ENSP00000399334.1
CENPJ	ENST00000616936.4	n.3042A>C		non_coding_transcript_exon_variant	Exon 10 of 16	1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.3042A>C		non_coding_transcript_exon_variant	Exon 10 of 18	2		ENSP00000441090.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	L;L;.
PhyloP100		0.21
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	.;N;N
REVEL	Benign	0.14
Sift	Benign	0.043	.;D;D
Sift4G	Benign	0.095	T;D;D
Polyphen		1.0	.;D;.
Vest4		0.79
MutPred		0.14		Gain of catalytic residue at S1019 (P = 0.0608);Gain of catalytic residue at S1019 (P = 0.0608);Gain of catalytic residue at S1019 (P = 0.0608);
MVP		0.61
MPC		0.54
ClinPred		0.94	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.069
Mutation Taster		=79/21	polymorphism

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: rs3742165; hg19: chr13-25466955;