dbSNP rs3780674: CDK5RAP2:c.4964-528G>A (chr9-120404641-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018249.6(CDK5RAP2):c.4964-528G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,010 control chromosomes in the GnomAD database, including 2,560 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2560 hom., cov: 32)

Consequence

CDK5RAP2
NM_018249.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0400

Publications

19 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

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	Effect	Exon Rank	Protein
CDK5RAP2	NM_018249.6	MANE Select	c.4964-528G>A	intron	N/A	NP_060719.4
CDK5RAP2	NM_001410994.1		c.4961-528G>A	intron	N/A	NP_001397923.1
CDK5RAP2	NM_001410993.1		c.4868-528G>A	intron	N/A	NP_001397922.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.4964-528G>A	intron	N/A	ENSP00000343818.4
CDK5RAP2	ENST00000360190.8	TSL:1	c.4727-528G>A	intron	N/A	ENSP00000353317.4
CDK5RAP2	ENST00000473282.6	TSL:1	n.*3788-528G>A	intron	N/A	ENSP00000419265.1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27203

AN:

151892

Hom.:

2561

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.270

Gnomad SAS

AF:

0.152

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.161

Gnomad OTH

AF:

0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.179

AC:

27221

AN:

152010

Hom.:

2560

Cov.:

AF XY:

0.179

AC XY:

13307

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.201

AC:

8333

AN:

41458

American (AMR)

AF:

0.199

AC:

3036

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

599

AN:

3468

East Asian (EAS)

AF:

0.270

AC:

1390

AN:

5146

South Asian (SAS)

AF:

0.153

AC:

736

AN:

4814

European-Finnish (FIN)

AF:

0.156

AC:

1645

AN:

10578

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.161

AC:

10967

AN:

67948

Other (OTH)

AF:

0.180

AC:

381

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1147

2294

3440

4587

5734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.166

Hom.:

1185

Bravo

AF:

0.183

Asia WGS

AF:

0.222

AC:

774

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.6

(source)

DANN

Benign

0.75

PhyloP100

-0.040

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over