rs17081389

Variant names:

• chr13-24912863-G-C
• rs17081389
• NM_018451.5:c.163C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018451.5(CPAP):​c.163C>G​(p.Pro55Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,614,104 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (135 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (154 hom.)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.349
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016890168).
• BP6: Variant 13-24912863-G-C is Benign according to our data. Variant chr13-24912863-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0814 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.163C>G	p.Pro55Ala	missense	Exon 2 of 17	NP_060921.3
	CPAP	NR_047594.2		n.330C>G		non_coding_transcript_exon	Exon 2 of 18
	CPAP	NR_047595.2		n.330C>G		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.163C>G	p.Pro55Ala	missense	Exon 2 of 17	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.163C>G		non_coding_transcript_exon	Exon 2 of 16	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.163C>G	p.Pro55Ala	missense	Exon 2 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3687 AN: 152114 Hom.: 135 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00680 AC: 1710 AN: 251402 AF XY: 0.00492

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00286 AC: 4178 AN: 1461872 Hom.: 154 Cov.: 32 AF XY: 0.00243 AC XY: 1767 AN XY: 727232

African (AFR) AF: 0.0909 AC: 3042 AN: 33476

American (AMR) AF: 0.00454 AC: 203 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5768

European-Non Finnish (NFE) AF: 0.000414 AC: 460 AN: 1112008

Other (OTH) AF: 0.00618 AC: 373 AN: 60394

GnomAD4 genome AF: 0.0243 AC: 3696 AN: 152232 Hom.: 135 Cov.: 32 AF XY: 0.0227 AC XY: 1689 AN XY: 74446

African (AFR) AF: 0.0837 AC: 3476 AN: 41522

American (AMR) AF: 0.00922 AC: 141 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68022

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.00432 Hom.: 21

Bravo AF: 0.0275

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0883 AC: 389

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00850 AC: 1032

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Microcephaly 6, primary, autosomal recessive (2)
-	-	1	Microcephaly 6, primary, autosomal recessive;C3888212:Seckel syndrome 4 (1)
-	-	1	Seckel syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.35
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.039
Sift	Benign	0.19	T
Sift4G	Benign	0.34	T
Polyphen		0.11	B
Vest4		0.13
MVP		0.52
MPC		0.23
ClinPred		0.0039	T
GERP RS		3.5
Varity_R		0.031
gMVP		0.17
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17081389; hg19: chr13-25487001;