13-24912965-T-C

Variant names:

• chr13-24912965-T-C
• rs35498994
• NM_018451.5:c.61A>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.61A>G​(p.Met21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,936 control chromosomes in the GnomAD database, including 17,819 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M21L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1599 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16220 hom.)
• Consequence: CPAP NM_018451.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 2.65
• Publications: 27 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=0.0048995316).
• BP6: Variant 13-24912965-T-C is Benign according to our data. Variant chr13-24912965-T-C is described in ClinVar as Benign. ClinVar VariationId is 21666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 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.61A>G	p.Met21Val	missense	Exon 2 of 17	NP_060921.3
	CPAP	NR_047594.2		n.228A>G		non_coding_transcript_exon	Exon 2 of 18
	CPAP	NR_047595.2		n.228A>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.61A>G	p.Met21Val	missense	Exon 2 of 17	ENSP00000371308.4	Q9HC77-1
	CPAP	ENST00000616936.4	TSL:1	n.61A>G		non_coding_transcript_exon	Exon 2 of 16	ENSP00000477511.1	Q9HC77-2
	CPAP	ENST00000926443.1		c.61A>G	p.Met21Val	missense	Exon 2 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20655 AN: 152102 Hom.: 1596 Cov.: 32

Gnomad AFR AF: 0.0989

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.149 AC: 37299 AN: 250918 AF XY: 0.143

Gnomad AFR exome AF: 0.0978

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.0454

Gnomad EAS exome AF: 0.334

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.144 AC: 211011 AN: 1461716 Hom.: 16220 Cov.: 33 AF XY: 0.141 AC XY: 102833 AN XY: 727156

African (AFR) AF: 0.0939 AC: 3145 AN: 33478

American (AMR) AF: 0.162 AC: 7260 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 1235 AN: 26134

East Asian (EAS) AF: 0.275 AC: 10932 AN: 39694

South Asian (SAS) AF: 0.0820 AC: 7072 AN: 86252

European-Finnish (FIN) AF: 0.202 AC: 10812 AN: 53406

Middle Eastern (MID) AF: 0.0560 AC: 323 AN: 5768

European-Non Finnish (NFE) AF: 0.145 AC: 161396 AN: 1111870

Other (OTH) AF: 0.146 AC: 8836 AN: 60396

GnomAD4 genome AF: 0.136 AC: 20666 AN: 152220 Hom.: 1599 Cov.: 32 AF XY: 0.137 AC XY: 10194 AN XY: 74426

African (AFR) AF: 0.0989 AC: 4107 AN: 41544

American (AMR) AF: 0.151 AC: 2308 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.319 AC: 1653 AN: 5178

South Asian (SAS) AF: 0.0935 AC: 452 AN: 4832

European-Finnish (FIN) AF: 0.193 AC: 2047 AN: 10584

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9566 AN: 68004

Other (OTH) AF: 0.132 AC: 278 AN: 2108

Alfa AF: 0.129 Hom.: 2121

Bravo AF: 0.137

TwinsUK AF: 0.148 AC: 547

ALSPAC AF: 0.135 AC: 522

ESP6500AA AF: 0.0958 AC: 422

ESP6500EA AF: 0.135 AC: 1162

ExAC AF: 0.144 AC: 17507

EpiCase AF: 0.130

EpiControl AF: 0.132

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.81	P
Vest4		0.29
MPC		0.12
ClinPred		0.065	T
GERP RS		5.3
Varity_R		0.77
gMVP		0.63
Mutation Taster		=97/3	polymorphism (auto)

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: rs35498994; hg19: chr13-25487103; COSMIC: COSV67883494;