9-120443634-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.3134G>C(p.Arg1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,972 control chromosomes in the GnomAD database, including 2,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1045K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.073 ( 773 hom., cov: 33)

Exomes 𝑓: 0.032 ( 1256 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.31

Publications

21 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=0.0011312366).

BP6

Variant 9-120443634-C-G is Benign according to our data. Variant chr9-120443634-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 link	c.3134G>C	p.Arg1045Thr	missense_variant	Exon 23 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.3134G>C	p.Arg1045Thr	missense_variant	Exon 23 of 38	1	NM_018249.6	ENSP00000343818.4		Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.0730

AC:

11100

AN:

152124

Hom.:

767

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0376

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.0410

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.0413

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0279

Gnomad OTH

AF:

0.0535

GnomAD2 exomes

AF:

0.0369

AC:

9282

AN:

251322

AF XY:

0.0326

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0383

Gnomad FIN exome

AF:

0.0383

Gnomad NFE exome

AF:

0.0286

Gnomad OTH exome

AF:

0.0356

GnomAD4 exome

AF:

0.0320

AC:

46716

AN:

1461730

Hom.:

1256

Cov.:

AF XY:

0.0306

AC XY:

22217

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.186

AC:

6223

AN:

33466

American (AMR)

AF:

0.0249

AC:

1112

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

391

AN:

26134

East Asian (EAS)

AF:

0.0685

AC:

2717

AN:

39686

South Asian (SAS)

AF:

0.00750

AC:

647

AN:

86258

European-Finnish (FIN)

AF:

0.0359

AC:

1916

AN:

53410

Middle Eastern (MID)

AF:

0.0496

AC:

286

AN:

5766

European-Non Finnish (NFE)

AF:

0.0280

AC:

31082

AN:

1111896

Other (OTH)

AF:

0.0388

AC:

2342

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

2358

4716

7075

9433

11791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1278

2556

3834

5112

6390

<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:

0.0731

AC:

11135

AN:

152242

Hom.:

773

Cov.:

AF XY:

0.0727

AC XY:

5409

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.185

AC:

7670

AN:

41512

American (AMR)

AF:

0.0375

AC:

574

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.0411

AC:

213

AN:

5178

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0413

AC:

438

AN:

10608

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0279

AC:

1901

AN:

68030

Other (OTH)

AF:

0.0581

AC:

123

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

478

956

1434

1912

2390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0310

Hom.:

145

Bravo

AF:

0.0797

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.182

AC:

801

ESP6500EA

AF:

0.0297

AC:

255

ExAC

AF:

0.0408

AC:

4948

Asia WGS

AF:

0.0670

AC:

231

AN:

3478

EpiCase

AF:

0.0270

EpiControl

AF:

0.0301

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 28, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary Microcephaly, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 3, primary, autosomal recessive

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.046

.;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.12

T;T;T;T

MetaRNN

Benign

0.0011

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.4

.;N;N;.

PhyloP100

1.3

PrimateAI

Benign

0.28

PROVEAN

Benign

0.69

.;N;N;N

REVEL

Benign

0.070

Sift

Benign

1.0

.;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;B;B

Vest4

0.067

MPC

0.11

ClinPred

0.0033

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

gMVP

0.069

Mutation Taster

=100/0

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