chr13-24905360-T-G

Variant names:

• chr13-24905360-T-G
• rs41306029
• NM_018451.5:c.2678A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018451.5(CPAP):​c.2678A>C​(p.Gln893Pro) 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 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.91
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20587704).

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.2678A>C	p.Gln893Pro	missense	Exon 7 of 17	NP_060921.3
	CPAP	NR_047594.2		n.2845A>C		non_coding_transcript_exon	Exon 7 of 18
	CPAP	NR_047595.2		n.2845A>C		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.2678A>C	p.Gln893Pro	missense	Exon 7 of 17	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.2678A>C		non_coding_transcript_exon	Exon 7 of 16	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.2678A>C	p.Gln893Pro	missense	Exon 7 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727194

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

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: 8.99e-7 AC: 1 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.048	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.027	D
Polyphen		0.076	B
Vest4		0.17
MutPred		0.28		Gain of catalytic residue at P896 (P = 2e-04)
MVP		0.82
MPC		0.15
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.22
gMVP		0.16
Mutation Taster		=85/15	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: rs41306029; hg19: chr13-25479498;