rs2501727

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018249.6(CDK5RAP2):c.2274T>C(p.Asp758Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,613,736 control chromosomes in the GnomAD database, including 16,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3729 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12567 hom. )

Consequence

CDK5RAP2
NM_018249.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.311

Publications

22 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 9-120458551-A-G is Benign according to our data. Variant chr9-120458551-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.311 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 link	c.2274T>C	p.Asp758Asp	synonymous_variant	Exon 20 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.2274T>C	p.Asp758Asp	synonymous_variant	Exon 20 of 38	1	NM_018249.6	ENSP00000343818.4		Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28339

AN:

151978

Hom.:

3708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.355

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.165

Gnomad ASJ

AF:

0.0856

Gnomad EAS

AF:

0.330

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.0980

Gnomad OTH

AF:

0.160

GnomAD2 exomes

AF:

0.147

AC:

36956

AN:

251390

AF XY:

0.141

show subpopulations

Gnomad AFR exome

AF:

0.365

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.0883

Gnomad EAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.125

GnomAD4 exome

AF:

0.115

AC:

168786

AN:

1461640

Hom.:

12567

Cov.:

AF XY:

0.115

AC XY:

83606

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.359

AC:

12003

AN:

33470

American (AMR)

AF:

0.155

AC:

6935

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0837

AC:

2187

AN:

26136

East Asian (EAS)

AF:

0.353

AC:

14027

AN:

39692

South Asian (SAS)

AF:

0.137

AC:

11788

AN:

86252

European-Finnish (FIN)

AF:

0.109

AC:

5844

AN:

53420

Middle Eastern (MID)

AF:

0.133

AC:

769

AN:

5768

European-Non Finnish (NFE)

AF:

0.0963

AC:

107020

AN:

1111788

Other (OTH)

AF:

0.136

AC:

8213

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

7790

15579

23369

31158

38948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4172

8344

12516

16688

20860

<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:

0.187

AC:

28408

AN:

152096

Hom.:

3729

Cov.:

AF XY:

0.188

AC XY:

13972

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.355

AC:

14734

AN:

41486

American (AMR)

AF:

0.164

AC:

2512

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0856

AC:

297

AN:

3470

East Asian (EAS)

AF:

0.330

AC:

1705

AN:

5164

South Asian (SAS)

AF:

0.146

AC:

704

AN:

4824

European-Finnish (FIN)

AF:

0.118

AC:

1248

AN:

10572

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0980

AC:

6665

AN:

67980

Other (OTH)

AF:

0.164

AC:

345

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1097

2194

3292

4389

5486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.125

Hom.:

3321

Bravo

AF:

0.198

Asia WGS

AF:

0.292

AC:

1018

AN:

3478

EpiCase

AF:

0.0983

EpiControl

AF:

0.101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2013

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

- -

Microcephaly 3, primary, autosomal recessive

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 28, 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 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.90

(source)

DANN

Benign

0.27

PhyloP100

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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