13-24912965-T-G

Variant names:

• chr13-24912965-T-G
• NM_018451.5:c.61A>C
• CPAP p.Met21Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018451.5(CPAP):​c.61A>C​(p.Met21Leu) 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. 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 Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M21V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2842117).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018451.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAP	NM_018451.5	MANE Select	c.61A>C	p.Met21Leu	missense	Exon 2 of 17	NP_060921.3
	CPAP	NR_047594.2		n.228A>C		non_coding_transcript_exon	Exon 2 of 18
	CPAP	NR_047595.2		n.228A>C		non_coding_transcript_exon	Exon 2 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAP	ENST00000381884.9	TSL:1 MANE Select	c.61A>C	p.Met21Leu	missense	Exon 2 of 17	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.61A>C		non_coding_transcript_exon	Exon 2 of 16	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.61A>C	p.Met21Leu	missense	Exon 2 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.79
gMVP		0.53
Mutation Taster		=97/3	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr13-25487103;