rs9511510

Variant names:

• chr13-24912773-G-T
• rs9511510
• NM_018451.5:c.253C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-24912773-G-T
• chr13-24912773-G-C

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.253C>A​(p.Pro85Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,613,882 control chromosomes in the GnomAD database, including 14,400 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (906 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13494 hom.)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.39
• Publications: 25 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=0.0021811724).
• BP6: Variant 13-24912773-G-T is Benign according to our data. Variant chr13-24912773-G-T is described in ClinVar as Benign. ClinVar VariationId is 158203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.141 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.253C>A	p.Pro85Thr	missense	Exon 2 of 17	NP_060921.3
	CPAP	NR_047594.2		n.420C>A		non_coding_transcript_exon	Exon 2 of 18
	CPAP	NR_047595.2		n.420C>A		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.253C>A	p.Pro85Thr	missense	Exon 2 of 17	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.253C>A		non_coding_transcript_exon	Exon 2 of 16	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.253C>A	p.Pro85Thr	missense	Exon 2 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes AF: 0.0997 AC: 15157 AN: 151992 Hom.: 907 Cov.: 32

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0917

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.0754

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.110 AC: 27651 AN: 251474 AF XY: 0.112

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.131 AC: 191389 AN: 1461772 Hom.: 13494 Cov.: 33 AF XY: 0.130 AC XY: 94171 AN XY: 727188

African (AFR) AF: 0.0304 AC: 1019 AN: 33478

American (AMR) AF: 0.104 AC: 4646 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3202 AN: 26134

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39698

South Asian (SAS) AF: 0.0825 AC: 7116 AN: 86254

European-Finnish (FIN) AF: 0.133 AC: 7087 AN: 53420

Middle Eastern (MID) AF: 0.115 AC: 661 AN: 5768

European-Non Finnish (NFE) AF: 0.144 AC: 160591 AN: 1111902

Other (OTH) AF: 0.117 AC: 7049 AN: 60394

GnomAD4 genome AF: 0.0996 AC: 15150 AN: 152110 Hom.: 906 Cov.: 32 AF XY: 0.0975 AC XY: 7245 AN XY: 74342

African (AFR) AF: 0.0363 AC: 1508 AN: 41488

American (AMR) AF: 0.0915 AC: 1398 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3470

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5190

South Asian (SAS) AF: 0.0751 AC: 361 AN: 4810

European-Finnish (FIN) AF: 0.126 AC: 1331 AN: 10570

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.143 AC: 9732 AN: 67984

Other (OTH) AF: 0.0989 AC: 209 AN: 2114

Alfa AF: 0.124 Hom.: 3947

Bravo AF: 0.0947

TwinsUK AF: 0.147 AC: 546

ALSPAC AF: 0.148 AC: 570

ESP6500AA AF: 0.0409 AC: 180

ESP6500EA AF: 0.138 AC: 1186

ExAC AF: 0.109 AC: 13260

Asia WGS AF: 0.0450 AC: 158 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.2
DANN	Benign	0.84
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.045
Sift	Benign	0.066	T
Sift4G	Benign	0.12	T
Polyphen		0.046	B
Vest4		0.033
MPC		0.15
ClinPred		0.0037	T
GERP RS		2.4
Varity_R		0.040
gMVP		0.16
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs9511510; hg19: chr13-25486911; COSMIC: COSV67884526;