chr9-120528758-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018249.6(CDK5RAP2):c.865G>C(p.Glu289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,606,270 control chromosomes in the GnomAD database, including 661,610 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 55080 hom., cov: 32)

Exomes 𝑓: 0.91 ( 606530 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 2.64

Publications

42 publications found

Variant links:

Genes affected

CDK5RAP2 (HGNC:18672): (CDK5 regulatory subunit associated protein 2) This gene encodes a regulator of CDK5 (cyclin-dependent kinase 5) activity. The protein encoded by this gene is localized to the centrosome and Golgi complex, interacts with CDK5R1 and pericentrin (PCNT), plays a role in centriole engagement and microtubule nucleation, and has been linked to primary microcephaly and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

CDK5RAP2 Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
microcephaly 3, primary, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
corpus callosum, agenesis of
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CDK5RAP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.7629204E-7).

BP6

Variant 9-120528758-C-G is Benign according to our data. Variant chr9-120528758-C-G is described in ClinVar as Benign. ClinVar VariationId is 21657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 link	c.865G>C	p.Glu289Gln	missense_variant	Exon 9 of 38	ENST00000349780.9	NP_060719.4	Q96SN8-1B3KVI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5RAP2	ENST00000349780.9 link	c.865G>C	p.Glu289Gln	missense_variant	Exon 9 of 38	1	NM_018249.6	ENSP00000343818.4		Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.843

AC:

128226

AN:

152030

Hom.:

55063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.681

Gnomad AMI

AF:

0.954

Gnomad AMR

AF:

0.856

Gnomad ASJ

AF:

0.929

Gnomad EAS

AF:

0.711

Gnomad SAS

AF:

0.871

Gnomad FIN

AF:

0.923

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.928

Gnomad OTH

AF:

0.866

GnomAD2 exomes

AF:

0.879

AC:

220722

AN:

251222

AF XY:

0.885

show subpopulations

Gnomad AFR exome

AF:

0.674

Gnomad AMR exome

AF:

0.858

Gnomad ASJ exome

AF:

0.925

Gnomad EAS exome

AF:

0.721

Gnomad FIN exome

AF:

0.929

Gnomad NFE exome

AF:

0.924

Gnomad OTH exome

AF:

0.903

GnomAD4 exome

AF:

0.912

AC:

1325495

AN:

1454122

Hom.:

606530

Cov.:

AF XY:

0.912

AC XY:

659984

AN XY:

723976

show subpopulations

African (AFR)

AF:

0.676

AC:

22504

AN:

33302

American (AMR)

AF:

0.856

AC:

38281

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.930

AC:

24251

AN:

26078

East Asian (EAS)

AF:

0.714

AC:

28301

AN:

39656

South Asian (SAS)

AF:

0.881

AC:

75852

AN:

86070

European-Finnish (FIN)

AF:

0.926

AC:

49453

AN:

53408

Middle Eastern (MID)

AF:

0.910

AC:

5228

AN:

5744

European-Non Finnish (NFE)

AF:

0.930

AC:

1028037

AN:

1105006

Other (OTH)

AF:

0.891

AC:

53588

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

5070

10140

15211

20281

25351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21318

42636

63954

85272

106590

<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:

0.843

AC:

128284

AN:

152148

Hom.:

55080

Cov.:

AF XY:

0.843

AC XY:

62682

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.681

AC:

28213

AN:

41440

American (AMR)

AF:

0.856

AC:

13093

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.929

AC:

3225

AN:

3470

East Asian (EAS)

AF:

0.712

AC:

3687

AN:

5182

South Asian (SAS)

AF:

0.871

AC:

4196

AN:

4818

European-Finnish (FIN)

AF:

0.923

AC:

9792

AN:

10604

Middle Eastern (MID)

AF:

0.895

AC:

263

AN:

294

European-Non Finnish (NFE)

AF:

0.928

AC:

63117

AN:

68024

Other (OTH)

AF:

0.865

AC:

1828

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

948

1896

2843

3791

4739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.909

Hom.:

47736

Bravo

AF:

0.831

TwinsUK

AF:

0.939

AC:

3480

ALSPAC

AF:

0.934

AC:

3600

ESP6500AA

AF:

0.693

AC:

3053

ESP6500EA

AF:

0.928

AC:

7981

ExAC

AF:

0.877

AC:

106466

Asia WGS

AF:

0.753

AC:

2619

AN:

3478

EpiCase

AF:

0.927

EpiControl

AF:

0.928

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 3, primary, autosomal recessive

Benign:3Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary Microcephaly, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T;.;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.77

T;T;T;T

MetaRNN

Benign

7.8e-7

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;L;L;.

PhyloP100

2.6

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.61

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.15

T;T;T;T

Sift4G

Uncertain

0.0070

D;D;D;.

Polyphen

0.90, 0.0030

.;P;B;.

Vest4

0.23

MPC

0.18

ClinPred

0.026

GERP RS

4.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.13

gMVP

0.22

Mutation Taster

=96/4

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over