rs116981543

Variant names:

• chr13-24912958-T-C
• rs116981543
• NM_018451.5:c.68A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018451.5(CPAP):​c.68A>G​(p.Asn23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,208 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (65 hom.)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0280
• Publications: 5 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=0.0038710237).
• BP6: Variant 13-24912958-T-C is Benign according to our data. Variant chr13-24912958-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00314 (478/152334) while in subpopulation EAS AF = 0.0237 (123/5182). AF 95% confidence interval is 0.0203. There are 8 homozygotes in GnomAd4. There are 271 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.68A>G	p.Asn23Ser	missense	Exon 2 of 17	NP_060921.3
	CPAP	NR_047594.2		n.235A>G		non_coding_transcript_exon	Exon 2 of 18
	CPAP	NR_047595.2		n.235A>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.68A>G	p.Asn23Ser	missense	Exon 2 of 17	ENSP00000371308.4
	CPAP	ENST00000616936.4	TSL:1	n.68A>G		non_coding_transcript_exon	Exon 2 of 16	ENSP00000477511.1
	CPAP	ENST00000926443.1		c.68A>G	p.Asn23Ser	missense	Exon 2 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 474 AN: 152216 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00674 AC: 1692 AN: 251084 AF XY: 0.00552

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0242

Gnomad FIN exome AF: 0.00458

Gnomad NFE exome AF: 0.000767

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00266 AC: 3886 AN: 1461874 Hom.: 65 Cov.: 32 AF XY: 0.00251 AC XY: 1828 AN XY: 727234

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.0258 AC: 1154 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26136

East Asian (EAS) AF: 0.0425 AC: 1687 AN: 39698

South Asian (SAS) AF: 0.00184 AC: 159 AN: 86254

European-Finnish (FIN) AF: 0.00530 AC: 283 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000383 AC: 426 AN: 1112002

Other (OTH) AF: 0.00225 AC: 136 AN: 60396

GnomAD4 genome AF: 0.00314 AC: 478 AN: 152334 Hom.: 8 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74498

African (AFR) AF: 0.000794 AC: 33 AN: 41574

American (AMR) AF: 0.0148 AC: 226 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0237 AC: 123 AN: 5182

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4832

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00145 Hom.: 4

Bravo AF: 0.00436

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00604 AC: 733

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Microcephaly 6, primary, autosomal recessive (1)
-	-	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	0.059
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.4
DANN	Benign	0.80
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.58	N
PhyloP100		0.028
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.068
Sift	Benign	0.49	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.19
MPC		0.098
ClinPred		0.0013	T
GERP RS		-2.7
Varity_R		0.021
gMVP		0.094
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs116981543; hg19: chr13-25487096;