dbSNP rs143258862: CPAP:p.Tyr341Asp (chr13-24907147-A-C) – 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.1021T>G(p.Tyr341Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00256 in 1,613,930 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 5 hom. )

Consequence

CPAP
NM_018451.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 4.76

Publications

5 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=0.035958022).

BP6

Variant 13-24907147-A-C is Benign according to our data. Variant chr13-24907147-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210653.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00165 (252/152340) while in subpopulation NFE AF = 0.00282 (192/68026). AF 95% confidence interval is 0.0025. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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.1021T>G	p.Tyr341Asp	missense	Exon 6 of 17	NP_060921.3
CPAP	NR_047594.2		n.1188T>G		non_coding_transcript_exon	Exon 6 of 18
CPAP	NR_047595.2		n.1188T>G		non_coding_transcript_exon	Exon 6 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPAP	ENST00000381884.9	TSL:1 MANE Select	c.1021T>G	p.Tyr341Asp	missense	Exon 6 of 17	ENSP00000371308.4	Q9HC77-1
CPAP	ENST00000616936.4	TSL:1	n.1021T>G		non_coding_transcript_exon	Exon 6 of 16	ENSP00000477511.1	Q9HC77-2
CPAP	ENST00000926443.1		c.1021T>G	p.Tyr341Asp	missense	Exon 6 of 18	ENSP00000596502.1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

253

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00282

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00150

AC:

378

AN:

251206

AF XY:

0.00160

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00276

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00266

AC:

3887

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

1866

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33476

American (AMR)

AF:

0.000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000244

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00332

AC:

3688

AN:

1111908

Other (OTH)

AF:

0.00174

AC:

105

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

181

363

544

726

907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00165

AC:

252

AN:

152340

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

124

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000721

AC:

AN:

41586

American (AMR)

AF:

0.00157

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00282

AC:

192

AN:

68026

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.00229

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00141

AC:

171

EpiCase

AF:

0.00262

EpiControl

AF:

0.00314

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

CENPJ-related disorder (1)

Microcephaly 6, primary, autosomal recessive (1)

not specified (1)

Seckel syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

M_CAP

Benign

0.019

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

PhyloP100

4.8

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.052

Polyphen

0.99

Vest4

0.68

MVP

0.67

MPC

0.71

ClinPred

0.032

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.67

gMVP

0.48

Mutation Taster

=76/24

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