dbSNP rs140927921: CPAP:p.Ala654Thr (chr13-24906078-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018451.5(CPAP):c.1960G>A(p.Ala654Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,612,736 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

CPAP
NM_018451.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -1.15

Publications

11 publications found

Variant links:

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

CPAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042422116).

BP6

Variant 13-24906078-C-T is Benign according to our data. Variant chr13-24906078-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158198.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00118 (179/152240) while in subpopulation NFE AF = 0.00191 (130/68008). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CPAP	NM_018451.5	MANE Select	c.1960G>A	p.Ala654Thr	missense	Exon 7 of 17	NP_060921.3
CPAP	NR_047594.2		n.2127G>A		non_coding_transcript_exon	Exon 7 of 18
CPAP	NR_047595.2		n.2127G>A		non_coding_transcript_exon	Exon 7 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPAP	ENST00000381884.9	TSL:1 MANE Select	c.1960G>A	p.Ala654Thr	missense	Exon 7 of 17	ENSP00000371308.4	Q9HC77-1
CPAP	ENST00000616936.4	TSL:1	n.1960G>A		non_coding_transcript_exon	Exon 7 of 16	ENSP00000477511.1	Q9HC77-2
CPAP	ENST00000926443.1		c.1960G>A	p.Ala654Thr	missense	Exon 7 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00125

AC:

314

AN:

250366

AF XY:

0.00125

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000870

Gnomad ASJ exome

AF:

0.00342

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00191

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00162

AC:

2364

AN:

1460496

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1137

AN XY:

726308

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33472

American (AMR)

AF:

0.00110

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00300

AC:

AN:

26020

East Asian (EAS)

AF:

0.000101

AC:

AN:

39680

South Asian (SAS)

AF:

0.000232

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00187

AC:

2079

AN:

1111164

Other (OTH)

AF:

0.00157

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00118

AC:

179

AN:

152240

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41550

American (AMR)

AF:

0.00150

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00191

AC:

130

AN:

68008

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00120

AC:

146

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00243

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly 6, primary, autosomal recessive (2)

not provided (1)

not specified (1)

Seckel syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.0070

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.0024

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0033

LIST_S2

Benign

0.52

M_CAP

Benign

0.0043

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

PhyloP100

-1.2

PrimateAI

Benign

0.24

PROVEAN

Benign

0.26

REVEL

Benign

0.010

Sift

Benign

0.89

Sift4G

Benign

0.55

Polyphen

0.0020

Vest4

0.013

MVP

0.18

MPC

0.12

ClinPred

0.0011

GERP RS

-4.1

Varity_R

0.018

gMVP

0.044

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over