Genetic Variant NM_018249.6:c.4821G>C (chr9-120407154-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018249.6(CDK5RAP2):c.4821G>C(p.Arg1607Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,614,042 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 55 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 47 hom. )

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.382

Publications

5 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:

ENSG00000301087 (HGNC:):

ENSG00000301087 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=0.0041181743).

BP6

Variant 9-120407154-C-G is Benign according to our data. Variant chr9-120407154-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2167/152294) while in subpopulation AFR AF = 0.0489 (2032/41550). AF 95% confidence interval is 0.0471. There are 55 homozygotes in GnomAd4. There are 1037 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 55 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018249.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDK5RAP2	NM_018249.6	MANE Select	c.4821G>C	p.Arg1607Ser	missense	Exon 32 of 38	NP_060719.4
CDK5RAP2	NM_001410994.1		c.4818G>C	p.Arg1606Ser	missense	Exon 32 of 38	NP_001397923.1
CDK5RAP2	NM_001410993.1		c.4725G>C	p.Arg1575Ser	missense	Exon 31 of 37	NP_001397922.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.4821G>C	p.Arg1607Ser	missense	Exon 32 of 38	ENSP00000343818.4
CDK5RAP2	ENST00000473282.6	TSL:1	n.*3645G>C		non_coding_transcript_exon	Exon 33 of 39	ENSP00000419265.1
CDK5RAP2	ENST00000480112.5	TSL:1	n.*2648G>C		non_coding_transcript_exon	Exon 32 of 38	ENSP00000418418.1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2165

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00367

AC:

922

AN:

251304

AF XY:

0.00257

show subpopulations

Gnomad AFR exome

AF:

0.0491

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00145

AC:

2119

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

901

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0492

AC:

1646

AN:

33480

American (AMR)

AF:

0.00284

AC:

127

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000105

AC:

117

AN:

1112004

Other (OTH)

AF:

0.00344

AC:

208

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

138

276

415

553

691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0142

AC:

2167

AN:

152294

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1037

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0489

AC:

2032

AN:

41550

American (AMR)

AF:

0.00569

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68026

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

107

215

322

430

537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00227

Hom.:

Bravo

AF:

0.0159

ESP6500AA

AF:

0.0440

AC:

194

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00437

AC:

531

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 25, 2015

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.

Apr 16, 2013

Genetic Services Laboratory, University of Chicago

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

CDK5RAP2-related disorder

Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

0.38

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.071

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

0.80

Vest4

0.46

MutPred

0.19

Gain of phosphorylation at R1607 (P = 0.0401)

MVP

0.33

MPC

0.091

ClinPred

0.034

GERP RS

1.0

Varity_R

0.19

gMVP

0.17

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over