NM_018249.6:c.480A>C

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.480A>C(p.Leu160Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,613,706 control chromosomes in the GnomAD database, including 6,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 685 hom., cov: 32)

Exomes 𝑓: 0.080 ( 6024 hom. )

Consequence

CDK5RAP2
NM_018249.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.55

Publications

25 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=-0.9).

BP6

Variant 9-120539068-T-G is Benign according to our data. Variant chr9-120539068-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 link	c.480A>C	p.Leu160Leu	synonymous_variant	Exon 6 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.480A>C	p.Leu160Leu	synonymous_variant	Exon 6 of 38	1	NM_018249.6	ENSP00000343818.4		Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.0762

AC:

11589

AN:

152154

Hom.:

686

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0408

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.111

Gnomad ASJ

AF:

0.0689

Gnomad EAS

AF:

0.290

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.0761

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0704

Gnomad OTH

AF:

0.0770

GnomAD2 exomes

AF:

0.0999

AC:

25121

AN:

251412

AF XY:

0.0996

show subpopulations

Gnomad AFR exome

AF:

0.0401

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.0739

Gnomad EAS exome

AF:

0.284

Gnomad FIN exome

AF:

0.0712

Gnomad NFE exome

AF:

0.0741

Gnomad OTH exome

AF:

0.0843

GnomAD4 exome

AF:

0.0797

AC:

116448

AN:

1461434

Hom.:

6024

Cov.:

AF XY:

0.0808

AC XY:

58736

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.0355

AC:

1187

AN:

33474

American (AMR)

AF:

0.125

AC:

5570

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

1800

AN:

26130

East Asian (EAS)

AF:

0.289

AC:

11454

AN:

39690

South Asian (SAS)

AF:

0.119

AC:

10279

AN:

86250

European-Finnish (FIN)

AF:

0.0739

AC:

3949

AN:

53402

Middle Eastern (MID)

AF:

0.0638

AC:

368

AN:

5768

European-Non Finnish (NFE)

AF:

0.0688

AC:

76509

AN:

1111632

Other (OTH)

AF:

0.0883

AC:

5332

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

5664

11328

16992

22656

28320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2936

5872

8808

11744

14680

<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:

0.0761

AC:

11583

AN:

152272

Hom.:

685

Cov.:

AF XY:

0.0793

AC XY:

5908

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0407

AC:

1692

AN:

41556

American (AMR)

AF:

0.111

AC:

1702

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

239

AN:

3468

East Asian (EAS)

AF:

0.290

AC:

1499

AN:

5176

South Asian (SAS)

AF:

0.130

AC:

628

AN:

4828

European-Finnish (FIN)

AF:

0.0761

AC:

807

AN:

10610

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0705

AC:

4793

AN:

68012

Other (OTH)

AF:

0.0762

AC:

161

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

529

1058

1588

2117

2646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0686

Hom.:

656

Bravo

AF:

0.0767

Asia WGS

AF:

0.208

AC:

724

AN:

3476

EpiCase

AF:

0.0707

EpiControl

AF:

0.0704

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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 02, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.049

(source)

DANN

Benign

0.34

PhyloP100

-5.5

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)

0.0

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