NM_018451.5:c.2210A>G

Variant names:

• chr13-24905828-T-C
• rs587783408
• NM_018451.5:c.2210A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018451.5(CPAP):​c.2210A>G​(p.Asp737Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D737A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.386
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022384316).

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.2210A>G	p.Asp737Gly	missense	Exon 7 of 17	NP_060921.3
	CPAP	NR_047594.2		n.2377A>G		non_coding_transcript_exon	Exon 7 of 18
	CPAP	NR_047595.2		n.2377A>G		non_coding_transcript_exon	Exon 7 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAP	ENST00000381884.9	TSL:1 MANE Select	c.2210A>G	p.Asp737Gly	missense	Exon 7 of 17	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.2210A>G		non_coding_transcript_exon	Exon 7 of 16	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.2210A>G	p.Asp737Gly	missense	Exon 7 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251396 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Microcephaly 6, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.65
DANN	Benign	0.065
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.39
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.047
MutPred		0.23		Loss of ubiquitination at K742 (P = 0.0345)
MVP		0.13
MPC		0.16
ClinPred		0.031	T
GERP RS		1.0
Varity_R		0.029
gMVP		0.049
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs587783408; hg19: chr13-25479966;