NM_018249.6:c.4041G>A

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.4041G>A(p.Leu1347Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,613,676 control chromosomes in the GnomAD database, including 2,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 1149 hom., cov: 33)

Exomes 𝑓: 0.033 ( 1569 hom. )

Consequence

CDK5RAP2
NM_018249.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.26

Publications

12 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=-0.89).

BP6

Variant 9-120419924-C-T is Benign according to our data. Variant chr9-120419924-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5RAP2	NM_018249.6 link	c.4041G>A	p.Leu1347Leu	synonymous_variant	Exon 27 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.4041G>A	p.Leu1347Leu	synonymous_variant	Exon 27 of 38	1	NM_018249.6	ENSP00000343818.4		Q96SN8-1

Frequencies

GnomAD3 genomes

AF:

0.0849

AC:

12903

AN:

152064

Hom.:

1141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0424

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.0418

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.0413

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0280

Gnomad OTH

AF:

0.0636

GnomAD2 exomes

AF:

0.0400

AC:

10058

AN:

251472

AF XY:

0.0349

show subpopulations

Gnomad AFR exome

AF:

0.230

Gnomad AMR exome

AF:

0.0258

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.0391

Gnomad FIN exome

AF:

0.0383

Gnomad NFE exome

AF:

0.0285

Gnomad OTH exome

AF:

0.0381

GnomAD4 exome

AF:

0.0331

AC:

48307

AN:

1461494

Hom.:

1569

Cov.:

AF XY:

0.0315

AC XY:

22884

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.229

AC:

7658

AN:

33456

American (AMR)

AF:

0.0273

AC:

1222

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0175

AC:

457

AN:

26132

East Asian (EAS)

AF:

0.0692

AC:

2748

AN:

39690

South Asian (SAS)

AF:

0.00764

AC:

659

AN:

86254

European-Finnish (FIN)

AF:

0.0359

AC:

1918

AN:

53420

Middle Eastern (MID)

AF:

0.0522

AC:

301

AN:

5768

European-Non Finnish (NFE)

AF:

0.0277

AC:

30788

AN:

1111674

Other (OTH)

AF:

0.0423

AC:

2556

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

2190

4381

6571

8762

10952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0851

AC:

12949

AN:

152182

Hom.:

1149

Cov.:

AF XY:

0.0840

AC XY:

6248

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.226

AC:

9367

AN:

41482

American (AMR)

AF:

0.0423

AC:

647

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.0419

AC:

217

AN:

5174

South Asian (SAS)

AF:

0.00685

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0413

AC:

438

AN:

10598

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0281

AC:

1909

AN:

68022

Other (OTH)

AF:

0.0682

AC:

144

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

544

1088

1631

2175

2719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0434

Hom.:

607

Bravo

AF:

0.0930

Asia WGS

AF:

0.0720

AC:

249

AN:

3478

EpiCase

AF:

0.0272

EpiControl

AF:

0.0299

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

- -

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. -

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

-0.89

CADD

Benign

0.10

(source)

DANN

Benign

0.48

PhyloP100

-1.3

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)

0.020

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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NM_018249.6:c.4041G>A

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