chr13-24906775-C-A

Variant names:

• chr13-24906775-C-A
• rs201088712
• NM_018451.5:c.1263G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PS1_Moderate PM2 BP4_Moderate

The NM_018451.5(CPAP):​c.1263G>T​(p.Gln421His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• Publications: 0 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.

• PS1: Transcript NM_018451.5 (CPAP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14368066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPAP	NM_018451.5	c.1263G>T	p.Gln421His	missense_variant	Exon 7 of 17	ENST00000381884.9	NP_060921.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPJ	ENST00000381884.9	c.1263G>T	p.Gln421His	missense_variant	Exon 7 of 17	1	NM_018451.5	ENSP00000371308.4
CENPJ	ENST00000616936.4	n.1263G>T		non_coding_transcript_exon_variant	Exon 7 of 16	1		ENSP00000477511.1
CENPJ	ENST00000545981.6	n.1263G>T		non_coding_transcript_exon_variant	Exon 7 of 18	2		ENSP00000441090.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	.;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;.
PhyloP100		0.15
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	.;N;N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	.;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.13	.;B;.
Vest4		0.21
MutPred		0.12		Loss of methylation at K423 (P = 0.0869);Loss of methylation at K423 (P = 0.0869);Loss of methylation at K423 (P = 0.0869);
MVP		0.42
MPC		0.15
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.32
gMVP		0.45
Mutation Taster		=61/39	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: rs201088712; hg19: chr13-25480913;