Genetic Variant CDK5RAP2:p.Ala1881Ser (chr9-120389277-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018249.6(CDK5RAP2):c.5641G>T(p.Ala1881Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1881P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDK5RAP2
NM_018249.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0390

Publications

1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
corpus callosum, agenesis of
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CDK5RAP2 links:

ENSG00000301087 (HGNC:):

ENSG00000301087 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.089473784).

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	UniProt
CDK5RAP2	NM_018249.6	MANE Select	c.5641G>T	p.Ala1881Ser	missense	Exon 38 of 38	NP_060719.4
CDK5RAP2	NM_001410994.1		c.5638G>T	p.Ala1880Ser	missense	Exon 38 of 38	NP_001397923.1	A0A8I5QKL1
CDK5RAP2	NM_001410993.1		c.5545G>T	p.Ala1849Ser	missense	Exon 37 of 37	NP_001397922.1	Q96SN8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK5RAP2	ENST00000349780.9	TSL:1 MANE Select	c.5641G>T	p.Ala1881Ser	missense	Exon 38 of 38	ENSP00000343818.4	Q96SN8-1
CDK5RAP2	ENST00000360190.8	TSL:1	c.5404G>T	p.Ala1802Ser	missense	Exon 37 of 37	ENSP00000353317.4	Q96SN8-4
CDK5RAP2	ENST00000473282.6	TSL:1	n.*4465G>T		non_coding_transcript_exon	Exon 39 of 39	ENSP00000419265.1	F8WF55

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460394

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726310

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111264

Other (OTH)

AF:

0.00

AC:

AN:

60336

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.8

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.54

M_CAP

Benign

0.0052

MetaRNN

Benign

0.089

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.039

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.90

REVEL

Benign

0.034

Sift

Benign

0.040

Sift4G

Benign

0.41

Polyphen

0.44

Vest4

0.16

MutPred

0.19

Gain of glycosylation at A1881 (P = 0.014)

MVP

0.27

MPC

0.069

ClinPred

0.096

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.083

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over