rs10220033

Variant names:

• chr13-24907740-C-T
• rs10220033
• NM_018451.5:c.974+278G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018451.5(CPAP):​c.974+278G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,042 control chromosomes in the GnomAD database, including 2,855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (2855 hom., cov: 32)
• Consequence: CPAP NM_018451.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.558
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-24907740-C-T is Benign according to our data. Variant chr13-24907740-C-T is described in ClinVar as Benign. ClinVar VariationId is 668867.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

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.974+278G>A		intron	N/A	NP_060921.3
	CPAP	NR_047594.2		n.1141+278G>A		intron	N/A
	CPAP	NR_047595.2		n.1141+278G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPAP	ENST00000381884.9	TSL:1 MANE Select	c.974+278G>A		intron	N/A	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.974+278G>A		intron	N/A	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.974+278G>A		intron	N/A	ENSP00000596502.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28207 AN: 151924 Hom.: 2847 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0923

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.213

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.186 AC: 28223 AN: 152042 Hom.: 2855 Cov.: 32 AF XY: 0.185 AC XY: 13780 AN XY: 74314

African (AFR) AF: 0.224 AC: 9276 AN: 41468

American (AMR) AF: 0.169 AC: 2573 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 792 AN: 3470

East Asian (EAS) AF: 0.0920 AC: 476 AN: 5176

South Asian (SAS) AF: 0.323 AC: 1558 AN: 4826

European-Finnish (FIN) AF: 0.113 AC: 1194 AN: 10562

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11620 AN: 67956

Other (OTH) AF: 0.220 AC: 466 AN: 2114

Alfa AF: 0.168 Hom.: 312

Bravo AF: 0.187

Asia WGS AF: 0.243 AC: 844 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs10220033;

hg19: chr13-25481878;